CK2 and protein kinases of the CK1 superfamily as targets for neurodegenerative disorders

Abstract

Casein kinases are involved in a variety of signaling pathways, and also in inflammation, cancer, and neurological diseases. Therefore, they are regarded as potential therapeutic targets for drug design. Recent studies have highlighted the importance of the casein kinase 1 superfamily as well as protein kinase CK2 in the development of several neurodegenerative pathologies, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. CK1 kinases and their closely related tau tubulin kinases as well as CK2 are found to be overexpressed in the mammalian brain. Numerous substrates have been detected which play crucial roles in neuronal and synaptic network functions and activities. The development of new substances for the treatment of these pathologies is in high demand. The impact of these kinases in the progress of neurodegenerative disorders, their bona fide substrates, and numerous natural and synthetic compounds which are able to inhibit CK1, TTBK, and CK2 are discussed in this review.

Introduction

Due to the fact that the world population is getting progressively older, the risk of neurodegenerative disorders (NDDs) is increasing. Those disorders occur when neurons lose their structure and function which finally leads to their death. Noteworthy, by 2000 it was estimated that the number of patients suffering from dementia in developed countries reached 13.5 million and will rise up to 36.7 million in 2050 (Zheng and Chen, 2022). Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most prevalent NDDs worldwide.

NDDs are classified according to their major clinical symptoms, altered proteins, and cellular/subcellular pathology. On the molecular level, typical features include protein misfolding and the formation of protein aggregates. The exact mechanisms for that are still unknown. These aggregates are the result of protein modification, like phosphorylation, sumoylation, and ubiquitination (Kovacs et al., 2010).

Typical characteristics of AD are senile plaques of amyloid-beta (Aβ) peptide precipitated in the space between neurons and the neurofibrillary tangles (NFTs) of fibrillar hyperphosphorylated tau protein (Glenner and Wong, 1984; Grundke-Iqbal et al., 1986). The Aβ peptide is the product of the proteolytic cleavage by β- and γ-secretases of the amyloid precursor protein (APP) (Vassar et al., 1999). In AD patients typical clinical features are the progressive loss of mental abilities, e.g., increasing forgetfulness, changes in personality, and cognitive difficulties. Additionally, as result of an immune response in the brain, nerve cells lose their function and die.

Huntington’s disease (HD) is caused by an autosomal dominant genetic defect. Mutations in the huntingtin gene (HTT) encoding huntingtin are responsible for the onset of HD. Typical features of this disease are movement disorders, like chorea and loss of coordination, as well as cognitive decline. Furthermore, common psychiatric symptoms are psychosis, depression, and obsessive-compulsive disorder (Rosenblatt, 2007). In HD patients a degeneration of the striatum and general shrinkage of the brain can be observed (Reiner et al., 1988). Loss of cortical mass is regionally selective and proceeds from posterior to anterior cortical regions during HD progression. Other symptoms are weight loss, cardiac failure, and skeletal-muscle wasting (Arenas et al., 1998; Aziz et al., 2008).

PD is a neurodegenerative disease characterized by progressive loss of neuromelanin containing dopaminergic neurons in the substantia nigra pars compacta. There is evidence for the relation between a small volume of this brain region and the weaker or less controlled motor movements of PD patients resulting in the often observed tremors (Menke et al., 2010). The pathological picture of PD includes motor impairments, like resting tremors, bradykinesia, postural instability, and rigidity. Due to the loss of norepinephrine non-movement related symptoms, like psychiatric problems, low blood pressure, and constipation, are seen. The cause of PD might be a combination of environmental and genetic factors.

Amyotrophic lateral sclerosis (ALS) is a fast progressive NDD affecting lower and upper neurons in the brain stem, spinal cord, and the motor cortex (Robberecht and Philips, 2013). It is the most common motor neuron disease in adults and the third most NDD worldwide (Renton et al., 2013). Typical features of ALS are atrophy and paralysis of skeletal muscles resulting from neuron loss and lack of communication between voluntary muscles of the body and the nervous system. Besides these symptoms, in most cases also cognitive and behavioral dysfunctions are present. ALS patients generally die within 3–5 years after first symptoms (Regal et al., 2006). The great majority of cases are classified as sporadic ALS, whereas only 10% are familial. Abnormal aggregations of transactive response DNA-binding protein 43 (TDP-43) are detected in almost all ALS cases (Neumann et al., 2006; Mackenzie et al., 2010). Mutations in the TARDBP gene encoding TDP-43 are associated with ALS (Sreedharan et al., 2008).

Protein kinases are encoded by about 2% of all human genes and are capable of phosphorylating up to 20% of all proteins. The counterplay of protein kinases and phosphatases regulates many processes in living cells through modification of serine, threonine and tyrosine residues (Hunter, 1995, 2012; Cohen, 2002; Schwartz and Murray, 2011; Nishi et al., 2014). As a result of phosphorylation protein activities, their stability, localization and interaction with other proteins are controlled. This posttranslational modification is capable of changing protein functions either by allosteric interaction or binding to regulatory domains (Jin and Pawson, 2012; Ardito et al., 2017). It has an important impact on processes, such as DNA replication, transcription and translation, cell metabolism, apoptosis, as well as stress and immunological response (Hunter, 1995; Cohen, 2002; Tarrant and Cole, 2009; Karve and Cheema, 2011). Proteins mainly undergo phosphorylation in the cytosol or in the nucleus (Duan and Walther, 2015).

Currently, there are no drugs available which cure or prevent NDDs, only acute disorders and symptoms are treated.

Numerous protein kinases have been described to play an important role in NDDs (Benn and Dawson, 2020). Unfortunately, most kinase inhibitors are not able to cross the blood-brain-barrier and are, therefore, only suitable for non central nervous disorders. During last decades, there is an increasing interest in the field to develop brain penetrant kinase inhibitors using the approaches from cancer research.

CK2 and protein kinases of the CK1 superfamily

Human protein kinases have been divided into 10 groups, 9 of them contain an eukaryotic kinase domain (ePK) and the last group is classified as atypical kinases. The majority of protein kinases phosphorylate serine and threonine residues (Ser/Thr kinases), others phosphorylate tyrosine (Tyr kinases). Few kinases are able to modify all three amino acids (dual-specificity kinases). Eukaryotic protein kinases share similarities in the primary sequences and structural features (Hanks and Hunter, 1995; Taylor et al., 1995; Taylor and Kornev, 2011).

CK1 isoforms together with the closely related vaccinia-related kinases (VRKs) and tau tubulin kinases (TTBKs) are classified in a separated group within the Ser/Thr kinase superfamily, whereas CK2 isoforms constitute a subclass of the CMGC group (Knippschild et al., 2005; Perez et al., 2011; Venerando et al., 2014; Fulcher and Sapkota, 2020). Protein kinases of the CK1 group and CK2 completely differ in their structure. At the beginning, they were named according to the phosphorylated in vitro protein substrate, casein. They were purified for the first time from soluble extracts of lactating bovine mammary (Waddy and Mackinlay, 1971). Natively isolated enzymes were purified on DEAE-cellulose and called casein kinase 1 and 2 depending on their elution profile (Hathaway and Traugh, 1979). G-CK or Fam20C shows high similarity to the casein kinase found in lactating mammary glands. It has been found in rat liver and brain and phosphorylates casein in the Golgi bodies (Bingham and Farrel, 1974; Lasa et al., 1997). Fam20C is characterized as a secretory kinase phosphorylating secreted proteins, from milk to bone proteins. This is important in the process of biomineralization of bones and teeth (Tagliabracci et al., 2015).

The role of CK1 in NDDs

CK1 is an evolutionarily conserved and ubiquitously expressed protein kinase. It belongs to second-messenger-independent and constitutively active kinases. CK1 exists in monomeric form with seven isoforms (α, β, γ1, γ2, γ3, δ, and ε) and their alternative splicing forms, which are encoded by different genes (Fulcher and Sapkota, 2020). The CK1 isoforms differ in their kinase activities, functions, subcellular localization, and biochemical properties (Zhang et al., 1996; Burzio et al., 2002; Takano et al., 2004; Xu et al., 2019). They vary in their molecular weights between 37 and 51 kDa with CK1α being the smallest and CK1γ3 the largest protein. The analysis of the substrate specificity of CK1 isoforms initially determined pS/pT-X_1-2-S/T as their consensus sequence. This led to the assumption that phosphorylation by CK1 depends on the prior phosphorylation of position −2 or −3 (Meggio et al., 1991; Meggio et al., 1992). Further studies have shown that this hypothesis did not hold true when proteins were efficiently phosphorylated without prephosphorylated residues (Flotow and Roach, 1991; Marin et al., 1994; Pulgar et al., 1999). Later, novel substrates were described containing a non-canonical motif (S-L-S) with acidic residues downstream of the phosphorylation site. Over 140 substrates are described for CK1. Most of them are involved in various cell processes, e.g., membrane transport and trafficking, microtubule-associated dynamics, apoptosis, and cell cycle progression (Yang et al., 2017; Xu et al., 2019). In diverse studies the important role of CK1 in NDDs was shown, emphasizing on tauopathies, such as AD. A distribution study of all CK1 isoforms comparing AD and control brains revealed that CK1 can be found in fibrillar lesions and, additionally, within the matrix of granulovacuolar degeneration bodies (Ghoshal et al., 1999; Kannanayakal et al., 2006). Contrary to CK1α which is linked to fibrillar lesions, CK1δ is linked to granulovacuolar degeneration bodies (Kannanayakal et al., 2006). It is possible that alteration of CK1δ function is aligned with dysregulation of circadian rhythms in AD. Elevated expression levels of CK1δ (33-fold) and CK1ε (9-fold) has been described in AD post-mortem brain tissue and ALS (Ghoshal et al., 1999; Yasojima et al., 2000; Salado et al., 2014; Palomo et al., 2020; Carter et al., 2021). Many proteins related to neurological disorders are modified by CK1α, e.g., β-secretase (Walter et al., 2001), α-synuclein (Mbefo et al., 2015), and parkin (Yamamoto et al., 2005). Similarly, it has been discovered that CK1δ phosphorylates several proteins that are associated with different NDDs in vitro. CK1δ phosphorylates the tau protein leading to its aggregation and finally the formation of neurofibrillary tangles (Li et al., 2004). Increased CK1 activity is associated with tau aggregation (Schwab et al., 2000). CK1δ-dependent phosphorylation has been also shown for other proteins connected with neurodegenerative diseases, e.g., presenilin-2, β-secretase, parkin, TDP43, α-synuclein, LRRK2, and tau (Okochi et al., 2000; Walter, 2000; Rubio de la Torre et al., 2009; Alquezar et al., 2016; Nonaka et al., 2016; Morales-Garcia et al., 2017; De Wit et al., 2018). Therefore, inhibition of CK1δ/ε has been described to possess favorable effects on ALS, frontotemporal dementia (FTD), and PD phenotypes in vivo (Perez et al., 2011; Salado et al., 2014; Alquezar et al., 2016; Cozza and Pinna, 2016; Jiang et al., 2018; Palomo et al., 2020).

The role of TTBK in NDDs

Within the CK1 superfamily a small family of brain-specific kinases phosphorylating microtubule-associated proteins tau and tubulin is classified (Ikezu and Ikezu, 2014). TTBK is a Ser/Thr and Tyr dual-kinase conducting multiple functions inside the cell. It comprises two isoforms: TTBK1 and TTBK2. TTBK1 was characterized as a neuron-specific kinase phosphorylating tau which leads to its aggregation, while TTBK2 was purified from the bovine brain (Takahashi et al., 1995; Sato et al., 2006). Both isoforms are encoded by distinctive genes, and furthermore, their localization in tissues is diverse (Nozal and Martinez, 2019). The sequence of TTBK1, consisting of 1321 amino acids, can be divided into kinase domain (residues 34-297), and a regulatory domain, which contains a characteristic 39 amino acids poly-Glu motif (Ikezu and Ikezu, 2014). The comparison of the TTBK1 and CK1δ kinase domain sequences revealed a 38% identity and 52% similarity (Sato et al., 2006). TTBK1 is primarily expressed in the human brain, notably in the adult brain cortex, cerebellum, and fetal brain. When mouse brain was analysed, TTBK1 was also detected in the frontal cortical layers, the hippocampus, and the granular layer of the cerebellum. Studies using antibodies confirmed the colocalization with tubulin in neurons (Sato et al., 2006). TTBK1 is upregulated in AD cases (Takashima et al., 1993).

TTBK2 consists of 1244 amino acids, and contrary to TTBK1, is ubiquitously expressed in the whole body. Highest TTBK2 mRNA expression levels are monitored in cerebellum Purkinje cells, granular cell layer, hippocampus, midbrain, and substantia nigra, whereas lower levels were found in the cortex of human, rat, and mouse brains (Houlden et al., 2007). In analyses of the protein expression in the brain and testis higher amounts of TTBK2 were found which correlates with higher activities of TTBK2 in these tissues (Bouskila et al., 2011). Mutations in the TTBK2 gene are responsible for the onset of spinocerebellar ataxia type 11, an NDD characterized by progressive ataxia and atrophy of the cerebellum and brainstem.

Both isoforms contain highly similar catalytic domains (88% identity and 96% similarity), but diverse C-terminal domains of 43% identity and 58% similarity (Ikezu and Ikezu, 2014; Nozal and Martinez, 2019). TTBK1/2 were described as kinases which show higher phosphorylation activity in case of a prephosphorylated substrate at position -3 (S/T-X-X-S/T/Y). On the surface of TTBK1 two positive sequences have been identified, which might act as putative binding sites for the prephosphorylated substrate (Xue et al., 2013; Kosten et al., 2014). Phosphorylation of tau was shown at Y197, S198, S199, S202, and S422, the critical sites in paired helical filaments (Grundke-Iqbal et al., 1986; Sato et al., 2006; Tomizawa et al., 2001). Interestingly, both isoforms differ in the aa sites which they phosphorylate. Due to tau phosphorylation in neurons at S422, TTBK1 is responsible for neurofibrillary pretangle formation and subsequent tau aggregation (Sato et al., 2008; Vazquez-Higuera et al., 2011; Yu et al., 2011; Lund et al., 2013). In knock-down experiments it has been demonstrated that TTBK1, not TTBK2, is the main isoform responsible for tau phosphorylation at S422 (Bao et al., 2021). Overexpression of TTBK1 in mice resulted in increased phosphorylation and oligomerization of tau in the brain (Xu et al., 2010).

Besides the phosphorylation of tau and tubulin by TTBK2, further substrates include centrosomal proteins CEP164 and CEP97, SV2A as well as neurodegeneration-associated protein TDP-43 (Takahashi et al., 1995; Tomizawa et al., 2001; Ikezu and Ikezu, 2014; Liachko et al., 2014; Liao et al., 2015; Zhang et al., 2015). Additionally, TTBK2 is crucial for the regulation of the growth of axonemal microtubules in ciliogenesis (Liao et al., 2015).

Especially TTBK1 is a promising candidate as target for NDDs treatment. It is mainly expressed in brain tissue, and therefore, possesses limited off-pathway roles. The phosphorylation of tau and TDP-43 makes it an ideal kinase in the case of these two proteinopathies.

The role of CK2 in NDDs

Together with CK1, CK2 was identified as phosphotranferase using casein as protein substrate for enzymes able to catalyse phosphate transfer from ATP to proteins (Burnett and Kennedy, 1954). Native protein kinase CK2 exists as a heterotetrameric holoenzyme consisting of two catalytic subunits, α and α′, and a dimer of regulatory subunits β (Hathaway and Traugh, 1979). The two isoforms of the CK2 catalytic subunit are highly homologous, but they are products of two different genes (Wirkner et al., 1994; Yang-Feng et al., 1994; Ackermann et al., 2005). CK2 subunits may build different active holoenzymes in three different conformations (αα′, α₂, or α′₂) or exist as free catalytic subunits. Each CK2 isoform possesses characteristics common for CK2, but differences in their substrate specificity and sensitivity to inhibitors have been described. They may also regulate different cellular processes (Pinna, 2002; Domańska et al., 2005; Janeczko et al., 2012).

CK2 is a constitutively active protein kinase, independent from second messengers, and is able to use both, ATP and GTP, as phosphoryl donors (Litchfield, 2003). Analysis of the eukaryotic phosphoproteome revealed that CK2 is responsible for the phosphorylation of almost one-quarter of phosphoproteins (Meggio and Pinna, 2003; Salvi et al., 2009; Franchin et al., 2015).

The minimal consensus sequence of CK2 was estimated as S/T-X-X-D/E/pS/pY, which is present in numerous proteins (Meggio et al., 1994; Venerando et al., 2014).

After the detection of the critical role in various disease states, like cancers and neurodegenerative disorders research groups worldwide focussed their attention on CK2 as a potential therapeutic target (Blanquet, 2000; Perez et al., 2011; Castello et al., 2017; Borgo et al., 2021a).

Several CK2 targets in NDDs were described. α-synuclein is phosphorylated at S129 that leads to aggregates which are the main component of Lewy bodies. In 90% of PD samples this phosphorylation is found, whereas in only 4% of normal tissue. As shown, this site is affected by several kinases and dependent on which one the biological effects might differ (Oueslati, 2016).

In different reports the diverse role of CK2 in AD is described. CK2 phosphorylates presenilin-2 at S7 and S9 in vitro while not altering APP cleavage by γ-secretase (Walter et al., 1996; Sannerud et al., 2016). Additionally, it was shown that CK2 phosphorylates SET, a phosphatase PP2A inhibitor, at position S9 which leads to its translocation to the cytoplasm (Zhang et al., 2018).

Numerous reports reveal that CK2 possesses a protective role in HD. The phosphorylation of huntingtin at S13 and S16 alters its location. Phospho-huntingtin is found in the nucleus which reduces its cellular toxicity (Atwal et al., 2011). Similarly, TDP-43 phosphorylation may prevent protein aggregation of truncated forms (Li et al., 2011).

Proteins involved in neurodegenerative diseases

A lot of NDD-associated proteins playing an important role in the onset of these disorders were identified (Kovacs et al., 2010): (1) the tubulin-associated unit (tau) protein; (2) amyloid-β (Aβ), peptides which result from cleavage of a large transmembrane precursor protein (Aβ-precursor protein or APP); (3) α-synuclein; (4) prion protein; (5) TDP-43 (Ou et al., 1995); (6) fused in sarcoma protein, Ewing’s sarcoma RNA-binding protein 1, and TATA-binding protein-associated factor 15, also known as FET proteins (Neumann et al., 2011). Other proteins are associated with neurological disorders caused by mutations leading to trinucleotide repeats (e.g., huntingtin, ataxins, atrophin-1).

Neurodegenerative proteinopathies can be classified according to the major protein involved in the disease: tauopathies, α-synucleinopathies, TDP-43 proteinopathies, FUS/FET proteinopathies, prion diseases, trinucleotide repeat diseases, neuroserpinopathy, ferritinopathy, and cerebral amyloidoses.

Several of these proteins were identified as substrates for CK1, TTBK, and CK2 and are further described below. Table 1 summarizes information about these proteins phosphorylated by CK1, TTBK, and CK2 and their respective phosphorylation sites.

α-synuclein

The name of this protein is derived from synaptic vesicles (syn-) and the nuclear envelope (-nuclein), both places where α-synuclein was first identified (Maroteaux et al., 1988). As we know now, this was probably the effect of a contaminated antibody that was used in this study. It is involved in PD, dementia with Lewy bodies, and multiple system atrophy (Spillantini et al., 1997; Wakabayashi et al., 1997; Gai et al., 1998). α-synuclein is a ubiquitously expressed protein with the highest levels in neurons, especially in presynaptic terminals. Other localizations for α-synuclein have been also identified, mainly based on overexpression experiments, but its function there remains unclear.

α-synuclein is a protein built of 140 amino acids that undergo posttranslational modification, especially at its C-terminus, e.g., phosphorylation, oxidation, ubiquitination, acetylation, and glycosylation. The major phosphorylation sites are S87 and S129 (Okochi et al., 2000; Fujiwara et al., 2002; Ishii et al., 2007). It was also shown that tyrosine residues are phosphorylated: Y125, Y133, and Y136 (Ellis et al., 2001; Nakamura et al., 2001; Negro et al., 2002). In pathological states, α-synuclein adopts a β-sheet conformation, which consequently leads to α-synuclein aggregation, fibril formation, and deposition into Lewy bodies (Conway et al., 1998; El-Agnaf et al., 1998; Narhi et al., 1999; Uversky, 2007; Yonetani et al., 2009). In PD, Lewy bodies, point mutations, and duplications/triplication of α-synuclein gene are the main pathological hallmark (Burré et al., 2018). Lewy bodies containing α-synuclein were also deteced in samples from familial AD patients (Lippa et al., 1998). Furthermore, in senil plaques in AD a short fragment of α-synuclein (aa residues 61-95) was found and termed non-Aβ-amyloid component, a region that is necessary for α-synuclein aggregation and fibrillogenesis (Ueda et al., 1993). Phosphorylation prevents or at least decreases the aggregation and toxicity of α-synuclein (Waxman and Giasson, 2008). Within all identified phosphorylation sites in vivo and in vitro only S87 lies in the non-Aβ-amyloid component (El-Agnaf et al., 1998).

Amyloid-beta precursor protein

APP was isolated and purified from cerebral Aβ deposits in 1984 (Glenner and Wong, 1984). It is found in different tissues, particularly in the brain, as a type I transmembrane protein located predominantly in the endoplasmic reticulum (Zheng and Koo, 2006). In 1992, Hardy and Higgins presented the amyloid cascade hypothesis as their theory of AD pathophysiology (Hardy and Higgins, 1992). Proteases from the secretase family (β-secretase and γ-secretase) cleave APP into Aβ peptides of different lengths, mainly Aβ38, Aβ40, and Aβ42, whereas α- and γ-secretases produce P3 peptides (LaFerla et al., 2007; O’Brien and Wong, 2011). Although the most abundant form is Aβ40 (80%–90%), Aβ42 is mainly responsible for protein aggregations and the formation of oligomers, amyloid fibrils, and amyloid plaques (Chen C et al., 2017). Those amyloid plaques are the cause of neurotoxicity in AD progression (Citron et al., 1996; Murphy and LeVine, 2010). Effects of Aβ40/Aβ42 aggregation, especially Aβ oligomers, are calcium dishomeostasis, disturbance of ion channels, alteration of glucose regulation and oxidative damage (Tiwari et al., 2019). Furthermore, it was described that Aβ aggregation promotes tau phosphorylation and aggregation. Out of 30 mutations described in the APP gene, 25 are involved in the deposition of insoluble Aβ, like KM670/671NL (Swedish), V717I (London), V717F (Indiana).

Tau protein

The tau protein was firstly discovered in porcine brain and isolated as heat-stable protein. The function of tau is the stabilization of internal microtubules (Weingarten et al., 1975). It is particularly highly expressed in axons of neuronal cells of the central nervous system (Binder et al., 1985). Studies have shown that tau is a phosphoprotein that then negatively influences the microtubule assembly by changes of the molecule shape (Jameson et al., 1980; Lindwall and Cole, 1984). Phosphorylation of tau is often accompanied by other posttranslational modifications, e.g., O-glycosylation, ubiquitination, and methylation. Tau inclusions occur in AD, Pick’s disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, Parkinsonism-dementia complex of Guam, and FTD (Lee et al., 2001).

Tau primary transcript generates six isoforms by alternative splicing resulting in proteins of 352-441 amino acids and MW of 45–65 kDa (Boyarko and Hook, 2021). Tau protein possesses 80 S/T and 5 Y residues of which at least 46 have been found to be phosphorylated in AD (Hanger et al., 2009). The total phosphorylation level of tau in AD and other tauopathies is several times higher than in control samples (Gong and Iqbal, 2008). The ability of tau to polymerize tubulin and to promote microtubule assembly is reduced through hyperphosphorylation (Yoshida and Ihara, 1993). A correlation between the level of hyperphosphorylation at multiple sites and the severity of NFT pathology was found which also correlates with the degree of neuronal loss and cognitive deficit (Grundke-Iqbal et al., 1986; Braak and Braak, 1991; Augustinack et al., 2002).

TDP-43

TDP-43 is a ubiquitous protein belonging to the ribonucleoprotein family and is normally localized in the nucleus where it takes part in RNA regulation (Nakielny and Dreyfuss, 1997; Geuens et al., 2016). Firstly, it was identified as a transcrptional repressor of HIV-1 transactivator response (TAR) long terminal repeats (Ou et al., 1995). Later, it was demonstrated that it is the major component of ubiquitinated inclusions in ALS and frontotemporal lobar degeneration (FTLD). Posttranslational modifications, such as cleavage, hyperphosphorylation, and ubiquitination lead to cytoplasmic accumulation and aggregation of TDP-43 (Arai et al., 2006; Neumann et al., 2006; Hasegawa et al., 2008). The sequence of TDP-43 is divided into three parts: an N-terminal domain (residues 1–103), two RNA recognition motifs (residues 104–200 and 191–262), and a C-terminal domain (residues 274–413). TDP-43 possesses 64 potential phosphorylation sites. Phosphorylation at S403/404 and S409/410 at the C-terminus results in pathological inclusions (Hasegawa et al., 2008; Inukai et al., 2008; Zhang et al., 2009). The N-terminus contains a nuclear localization sequence that is prone to mutations leading to cytoplasmic localization of TDP-43 and aggregation, whereas the C-terminus is necessary for solubility and cellular localization (Ayala et al., 2008; Barmada et al., 2010).

Parkin

Parkin possesses an activity of an E3 ubiquitin ligase (Shimura et al., 2000). Insoluble parkin, resulting from point mutations, plays a major role in the inactivation of the protein in PD (Cookson et al., 2003; Sriram et al., 2005; Hampe et al., 2006). Phosphorylation of S101, S127, and S378 was identified using CK1 in vitro and in vivo with HEK293T cells transiently transfected with parkin (Yamamoto et al., 2005; Rubio de la Torre et al., 2009). Treatment of those cells with IC261, a selective CK1 inhibitor, significantly decreased the phosphorylation level of parkin (Mashhoon et al., 2000; Bain et al., 2007; Rubio de la Torre et al., 2009). Another potent CK1 inhibitor, D4476, was used, which confirmed the hypothesis that S101 and S378 are phosphorylated in vivo. Besides CK1, parkin is phosphorylated by CDK5 at S121 (Avraham et al., 2007). Experiments in vivo and in vitro have shown that the interplay of CK1 and CDK5 is necessary for efficient phosphorylation by both kinases. A phospho-mimetic mutant on the phosphorylation site of one kinase increased the phosphorylation level by the second kinase. Supporting evidence is the finding that roscovitine, a selective CDK5 inhibitor, reduced the phosphorylation of parkin by CK1 resulting from inhibition of S121 phosphorylation (Meijer et al., 1997; Rubio de la Torre et al., 2009). In further experiments, the influence of parkin phosphorylation on its activity and its effect on the formation of inclusions was examined. The results indicate that the phospho-mimetic mutant for compound phosphorylation possesses slightly enhanced enzymatic activity and showed a significantly higher tendency for aggregation (Rubio de la Torre et al., 2009).

Huntingtin

Huntingtin is a ubiquitously expressed protein with a molecular weight of 350 kDa. It possesses a poly-Glu sequence at the N-terminus containing up to 35 CAG repeats in wild-type, whereas HD patients carry 36 or more repeats (Rubinsztein et al., 1996). There is evidence for an inverse correlation between the age of onset of symptoms and the number of CAG repeats (Andrew et al., 1993). In 65%–71% of cases, larger CAG repeats led to earlier ages of onset. Genetic and environmental factors are also playing an important role in the age of onset. Huntingtin is localized in the cytoplasm, partially in the nucleus. Its nuclear localization sequence is also found in the N-terminus and in the C-terminus a nuclear export sequence is found (Xia et al., 2003; Desmond et al., 2012). The prolongated poly-Glu sequence in HD patients inhibits the interaction between the N-terminus with the nuclear pore protein translocated promotor region which is involved in nuclear export. As a result, huntingtin is accumulated in the nucleus (Cornett et al., 2005). Noteworthy, toxic fragments of huntingtin present in the nucleus are mainly from the mutated protein due to their higher concentration in the nucleus than in the cytoplasm (Hackam et al., 1998; Lunkes et al., 2002). One therapeutic strategy is the inhibition of the formation of these fragments by modification of huntingtin (e.g., phosphorylation) to prevent the cleavage of the protein (Atwal et al., 2011).

Ataxin-3

Ataxin-3 is a ubiquitin protease involved in transcriptional regulation and the disease protein in spinocerebellar ataxia type 3 (Burnett et al., 2003; Evert et al., 2006). It possesses nuclear and cytoplasmic functions. Its subcellular distribution is regulated through phosphorylation. As in the case of huntingtin, the nuclear presence of ataxin-3 represents a key element in the accumulation of toxic fragments (Bichelmeier et al., 2007). Analysis of 15 putative serine phosphorylation site mutants revealed that S236 in the first ubiquitin-interacting motif (UIM), S256 and S260/261 in the second UIM, as well as S340 and S352 in the third UIM, are the major phosphorylation sites of CK2 (Mueller et al., 2009). Phosphorylation of those serines determines the subcellular location of ataxin-3. Modulation of S340, S352, and S236 increases the nuclear presence of ataxin-3, while phosphorylation of S256 and S260/261 provides preferential cytoplasmic localization (Mueller et al., 2009). Apart from the influence on the cellular distribution of ataxin-3, phosphorylation plays also an important role in the solubility of the protein. As shown in vivo experiments phospho-mimetic mutants formed aggregates in the nucleus (Mueller et al., 2009). The effect of two selective CK2 inhibitors (DMAT and TBB) on the localization and presence of inclusions was examined in cell culture (Pagano et al., 2008). Inhibition of CK2 resulted in lower nuclear localization of ataxin-3 and less formation of protein aggregates (Mueller et al., 2009).

Presenilin-2

PSEN1 and PSEN2 genes, containing 10 exons, encode presenilin-1 and presenilin-2, respectively, which play important roles in AD pathogenesis. Presenilin is a part of the γ-secretase complex responsible for the cleavage of APP to generate Aβ peptides. Mutations in PSEN1/2 and deletions leading to alternative transcripts are associated with AD and FTD (Raux et al., 2000; Evin et al., 2002; Marcon et al., 2009). Incorrect transcripts, like PS2V lacking exon 6, are related to different diseases, e.g., AD (Braggin et al., 2019). PS2V produces truncated presenilin-2 containing 124 amino acids and only 1 of 9 transmembrane domains. This isoform was identified in the brain of AD patients with elevated levels leading to an increased amount of Aβ peptide (Sato et al., 1999; Smith et al., 2004). Two phosphorylation sites for CK2 (S7 and S9) and one for CK1 (S19) were identified (Walter et al., 1996). S19 phosphorylation elevated the binding of AP-1 protein to presenilin-2, whereas S7 and S9 phosphorylation did not show any change in the binding of activator protein 1 (Sannerud et al., 2016). Further experiments are necessary to examine the role of phosphorylation in the case of presenilin-2.

Inhibitor-2 PP2A

The phosphorylation of tau is regulated by phosphoseryl/phosphothreonyl protein phosphatase PP2A and its activity is decreased in AD brain. PP2A is regulated by two endogenous inhibitory proteins called I₁^PP2A and I₂^PP2A (Gong et al., 1993; Li et al., 1996). Typically, I₂^PP2A is mainly located in the nucleus regulating DNA replication, gene transcription, cell-cycle progression, DNA repair and migration as well as chromatin remodeling. In AD patients, I₂^PP2A is overexpressed and translocated from the nucleus into the cytoplasm, where PP2A and significantly hyperphosphorylated tau is localized forming the NFTs in the neuronal cytoplasm (Tanimukai et al., 2005). In PC12 cells, stably transfected with tau and transiently transfected with human I₂^PP2A, accumulation of the inhibitor in the cytoplasm was observed (Chohan et al., 2006). CK2 was identified as one of two kinases responsible for the phosphorylation of S9 (Vera et al., 2007). This phosphorylation affects the ability of I₂^PP2A to bind to importin proteins (importin-α and importin-β). Phosphorylated I₂^PP2A does not form a complex with importin, therefore, it is localized in the cytoplasm instead to be transported into the nucleus (Yu et al., 2013).

Kinase inhibitors used in NDD pathway interrogation

In the literature synthetic and natural substances are described inhibiting protein kinases CK1, TTBK, and CK2. Table 2 gives an overview of several inhibitors with in vitro and/or in vivo activities on these kinase targets. Many of them do not selectively inhibit kinases, but might be a good starting point for drug design. Many research results on cancers and cancer cell lines involving protein kinase inhibitors were published, but only a few reports towards NDDs, especially in the case of CK2. Cancer and NDDs are both characterized by the dysregulation of the same signalling pathways, but with opposite effects. In cancers the cell survival and proliferation is increased, whereas, in NDDs those alterations lead to cell death and apoptosis. The most altered signal pathways in cancer, e.g., Nrf2 pathway and Wnt/β-catenin pathway, are also implicated in NDDs, like AD and PD (Varela and Garcia-Rendueles, 2022).

TABLE 2

Inhibitor name and structure	Biological activity	References
CK1 inhibitors
	- heterocyclic, central nervous system (CNS)-penetrating, and ATP-competitive inhibitors of CK1δ (IC50 values of 23 nM and 47 nM)	Alquezar et al. (2016); Martínez-González et al. (2020); Morales-Garcia et al. (2017); Posa et al. (2019); Salado et al. (2014)
.	- selective over a 456 kinases panel
	- decrease of TDP-43 phosphorylation in cell culture assays
IGS-2.7	- able to prolongate the Drosophila lifespan by inhibition of TDP-43 neurotoxicity
.	- IGS-2.7 possesses protective activity on dopaminergic neurons induced by 6-hydroxy dopamine (6-OHDA) and reduces the lipopolysaccharide inflammatory activation in primary cell cultures of astrocytes and microglia
IGS-3.27	- effect on cell proliferation, TDP-43 phosphorylation, and subcellular localization
	- effect on TDP-43 dependent repression of CDK6 expression
	- progranulin-deficient cells treated with 5 μM IGS-2.7 led to a potent inhibition of TDP-43 phosphorylation and normalization of the abnormal cytosolic TDP-43 accumulation
	- expression of CDK6 mRNA and the amount of TDP-43 was decreased by IGS-2.7
	- IGS-2.7 prevented cytosolic TDP-43 accumulation in a human neuroblastoma SH-SY5Y cell model through CK1δ inhibition
	- able to reduce TDP-43 phosphorylation in human cells derived from FTD and ALS patients
	- IGS-2.7 is active in a TDP-43 transgenic mouse (A315T) model and in a human cell-based model of ALS
. PF-4800567	- selective ATP-competitive CK1 inhibitor- higher inhibitory activity towards CK1 than towards CK1δ with IC50 values of 32 and 711 nM as well as IC50 values of 2.65 and 20.38 in whole cells, respectively- blocks period protein 3 (PER3) nuclear localization mediated by CK1 (0.01-10 ) and suppresses PER2 degradation at - rapid absorption and distribution in the plasma and brain of mice- extension of the period for single phases of the molecular clockwork, especially the duration of PER2-mediated transcriptional feedback	Meng et al. (2010); Walton et al. (2009)
.	- effective and selective inhibitor of CK1ε and CK1δ (IC50 values of 7.7 nM and 14 nM, respectively)	Adler et al. (2019); Badura et al. (2007); Cheong et al. (2011); Sundaram et al. (2019)
PF-670462	- influence on the localization of the GFP signal back to the cytoplasm dependent on the inhibitor concentration, with an EC50 of 290±39 nM in CKIε-transfected COS7 cells
	- a potent inhibitor of the Wnt/β-catenin signaling pathway with an IC50 of ∼17 nM
	- weak inhibition of cell proliferation and only moderately inhibition of HEK293 and HT1080 cell growth (1 μM)
	- potential to repeal hippocampal proteomic changes in several AD-related and clock-regulated pathways, e.g., synaptic plasticity and APP cleavage
	- able to reverse effects of working memory deficits and lead to the improvement of disturbances in behavioral circadian rhythm
	- inhibition of CK1δ/ε increases the cognitive-affective behavior and inhibits the amyloid amount in the APP-PS1 mouse model of AD
. PF-5006739	- possesses strong and selective potency against CK1δ and CK1ɛ in enzymatic assays (3.9 nM and 17 nM, respectively) and in whole-cell screening (EC50 = 15.2 and 83 nM, respectively)- in a panel of 59 kinases, only JNK2 and MAP4K6 are inhibited at a concentration of 1 µM with IC50 values of 6.1 and 1.5 µM, respectively- used in the treatment of several psychiatric disorders- lowers the effect on opioid drug-seeking behavior in a rodent operant reinstatement animal model dependent on the inhibitor dose- daily treatment of diet-induced obese and ob/ob mice increase expression of clock genes and improved the glucose tolerance	Cunningham et al. (2016); Wager et al. (2014)
.	- effective ATP-competitive CK1 inhibitor (IC50 values of 44 nM for CK1δ and 260 nM for CK1ε)- EC50 value below 100 nM estimated in a MTT assay against human melanoma cell line A375- a binding assay analysis of 442 kinases showed that only CK1δ and CK1ε are strongly inhibited- reduction of the activities of CDK6/cyclin D3, CDK6/cyclin D1, CDK4/cyclin D3, CDK4/cyclin D1, and FLT3 (IC50 values between 368 and 3,000 nM)- decrease of TPA-induced skin tumor formation in carcinogen-initiated mouse skin cells, most likely by the inhibition of the Wnt/β-catenin signaling	Bibian et al. (2013); Su et al. (2018)
SR-3029
. LH846	- selective, cell-permeable, ATP-site-targeting inhibitor (IC50 values of 290 nM, 1.3 and 2.5 CK1δ, , and - inhibition of PER1 phosphorylation by CK1δ and its degradation- able to prolongate the circadian period in U2OS cells, but only minimally effects the amplitude	Lee et al. (2011)
.	- effective, reversible, and weakly specific ATP-competitive inhibitor of CK1δ and ALK5 with IC50 values of 0.3 and 0.5 µM, respectively	Flajolet et al. (2007); Järås et al. (2014); Liu et al. (2021); Rena et al. (2004)
D4476	- modest inhibitory activity against other kinases, including p38α MAP kinase, PKB, SGK, and GSK-3β- potently kills leukemia stem cells (LSCs) with high selectivity when compared to normal HSPCs- CK1α inhibition causes a decrease of ribosomal protein S6 phosphorylation and activates p53 resulting in the selective removal of leukemia cells
	- inhibition or down-regulation of CK1α, efficiently reduced glioblastoma multiforme (GBM) cell proliferation in both Tp53 wild-type and Tp53-mutant GBM cells
	- significant reduction of Aβ40 peptide production in N2A cells expressing APP-695
	- effect towards γ-secretase cleavage activity in mammalian cells transfected with the C-terminal fragment of APP
.	- compound 1: ATP-competitive and isoform CK1δ seletive inhibitor (Ki = 125 nM)	Cozza et al. (2008)
Amino-antraquinone 1	- compound 2: inhibitory activity against CK1δ (IC50 = 0.6 μM)- cytotoxicity of compound 1 on human ovarian carcinoma cell line 2008 (IC50 = 14.4 μM) and on its cisplatin-resistant clone C13 ( IC50 = 87.9 μM)- cytotoxicity of compound 2 on human ovarian carcinoma cell line 2008 (IC50 = 122.4 μM) and on its cisplatin-resistant clone C13 ( IC50 = 8.0 μM)
.
Amino-antraquinone 2
.	- highly effective ATP-competitive inhibitor of CK1δ (IC50 CK1δ=4 nM, IC50 CK1ε=25 nM)- highly selective towards CK1δ when tested against more than 321 protein kinases- high efficiency against p38α MAPK with an IC50 value three-fold higher compared to CK1δ- inhibitory effect on human pancreatic cancer cell lines Colo357 and Panc89 (EC50 of 3.5 and 1.5 μM, respectively)	Halekotte et al. (2017)
Compound 11b
.	- potent ATP-competitive and specific inhibitors of CK1δ (IC50 values of 40 and 42 nM, respectively)	Bischof et al. (2012)
Bischof-5	- Bischof-5 exhibits a 5-fold higher affinity towards CK1δ than to CK1ε (IC50=199 nM)
	- Bischof-6 inhibits both isoforms in similar range (IC50=33 nM for CK1ε)
.	- Bischof-5 is highly potent and selective towards CK1δ in a panel of 442 kinases
Bischof-6	- Bischof 5 and 6 negatively influence the proliferation of several tumor cell lines
.	- potent ATP-competitive and selective CK1δ/ε inhibitors (IC50 values of 0.07-0.81 μM and 0.13-1.36 μM)	Richter et al. (2014)
Compound 1
.	- inhibition of growth analysed by cell viability assays and cell cycle distribution on 82 different tumor cell lines
Compound 2
.	- ATP-competitive and CK1 specific	García-Reyes et al. (2018)
IWP-2	- specifically inhibits CK1δ when compared to 320 other kinases (IC50 values of 0.317 and 4 μM for CK1δ and CK1ε, respectively- inhibition of the gatekeeper mutantM82FCK1δ (IC50 = 40 nM)- inhibition of the viability of various cancer cell lines
.	- multi-kinase inhibitor (IC50 values between 0.5 and 20 nM for CK1 isoforms, CDK7, and CDK9)	Ball et al. (2020)
BTX-A51	- specifically blocks leukemic stem cell target CK1α as well as CDK7 and CDK9 preventing transcription of key oncogenic genes.
	- activation of p53 and its sustained stabilization by a super-enhancer shutdown of Mdm2 in combination with the transcriptional shutdown of leukemia oncogenes, including Myc and Mcl1
.	- highly selective and CK1 isoform-specific (IC50 = 14 nM for CK1γ)	Hua et al. (2012)
Compound 1h	- excellent selectivity over other CK1 isoforms, like CK1α (IC50 = 9.18 μM) and CK1δ (IC50 = 2.32 μM)
	- no inhibitory activity against 48 kinases including GSK3β (IC50 = 60 μM)
	- stable in the rat and human microsomes and show good effects on cells and modest pharmacokinetic properties in rats
.	- inhibitory activity against CK1δ and CK1ε (IC50 values of 0.41 and 0.8 μM, respectively)	Baunbæk et al. (2008); Iwao et al. (2011)
Lamellarin 3	- inhibition of other kinases (CDKs, DYRK1A, GSK3α/β, and PIM1) with IC50 values from 0.06–0.6 μM
.	- inhibition of cell survival of human neuroblastoma SH-SY5Y cells (IC50 values of 0.56 and 0.11 μM for lamellarin 3 and 6, respectively)
Lamellarin 6
.	- inhibitory activity in nanomolar range against few AD-related protein kinases, e.g., CK1δ, GSK3β, and CDK5/p25 (IC50 values of 35, 10, and 28 nM, respectively)	Meijer et al. (2000); Plisson et al. (2014); Wan et al. (2004); Zhang et al. (2012)
Hymenialdisine	- numerous kinases were inhibited only in the micromolar range, e.g., Aurora-A, Her1/2, IKKα, PKA, and PKB- CK1 dose-dependent inhibition of presenilin-2 phosphorylation using presenilin-2-maltose-binding protein- debromohymenialdisine inhibits the activities of diverse protein kinases including CK1δ, CDK5/p25, and GSK3β (IC50 values of 0.1–0.4 μM
TTBK1/2 inhibitors
.	- potent and selective ATP-competitive inhibitors (IC50 values of 4.4 µM and 6.8 µM (AZ-1), 2.6 µM and 3.2 µM (AZ-2) for TTBK1 and TTBK2, respectively)	Xue et al. (2013); Kiefer et al. (2014); Palomo et al. (2020)
AZ-1	- neuroprotective profile on phospho-TDP-43 induced cell death in cellular human neuroblastoma models
.
AZ-2
.	- potent, selective and brain-penetrant TTBK1 inhibitor (IC50 = 2.7 nM)	Dillon et al. (2020); Halkina et al. (2021); Tian et al. (2021)
TTBK1-IN-1	- in in vivo selectivity study with a panel of 150 kinases only 4 kinases (including TTBK1/2) are inhibited more than 50%- dose-dependent inhibition of tau phosphorylation levels at Ser422 (IC50 of ∼9.5 nM) in isoflurane-induced hypothermia mice model- reduction of TDP-43 phosphorylation and formation of high molecular species in N2a cells
.	- potent, selective and brain penetrant inhibitors of TTBK1 (IC50 of 60 nM (compound 8) and 2.7 nM (compound 31))	Halkina et al. (2021)
Compound 8	- compound 31 inhibits tau phosphorylation at S422 in mouse hypothermia and a rat developmental model (IC50 of 315 nM)
.
Compound 31
.	- cell-permeable, ATP-competitive TTBK1/2 inhibitor (IC50 values of 0.24 μM and 4.2 μM for TTBK1 and TTBK2, respectively)	Nozal et al., (2022)
Pyrropirimidine 29	- inhibition of TDP-43 phosphorylation in vitro and in vivo, in cell cultures and in the spinal cord of transgenic TDP-43 mice
.	- possesses good CNS penetrating properties and potent antioxidant and anti-inflammatory activities	Jana and Singh, (2020); Wang et al. (2016)
5-TDMF	- inhibition of LPS-induced NF-κB translocation and expression of iNOS and COX-2 blocking MAP kinase and Erk signaling pathways
.	- inhibition of TTBK1 and TTBK2 (1 μM) with remaining activity of 8% and 12% (MRC Kinase Profiling Inhibitor Database)	Potjewyd et al. (2022)
AMG-28	- inhibition of tau phosphorylation at S422 in a biochemical and cellular assay with IC50 values of 199 nM and 1.85 μM, respectively
	- new analogs are more potent inhibitors of TTBK2 than TTBK1
	- assayed in NanoBRET test in permeabilized HEK293 cells and compound 9 shows IC50 values of 2.5 and 1.8 μM for TTBK1 and TTBK2, respectively- in an enzymatic test derivative 9 possesses inhibitory activity (IC50 values between 150 and 400 nM)- derivative 9 shows highest kinome-wide selectivity towards the TTBK activities
CK2 inhibitors
.	- cell-permeable, highly selective, and ATP/GTP-competitive inhibitor of CK2 (IC50 values of 0.9 and 1.6 μM for rat liver and human recombinant CK2, respectively)	Pagano et al. (2008); Sarno et al. (2001); Szyszka et al. (1995); Yadikar et al. (2020); Zhang et al. (2018)
TBB	- discrimination between CK2 subunits (Ki values ranging from 80 nM to 210 nM)
	- strong inhibition of several other kinases (DYRK1-3, HIPK2, and PIM1–3) at a concentration of 10 μM
	- effect on human prostate cancer PC-3 cell viability is dependent on the time of administration
	- inhibition of okadaic acid-induced monomeric and oligomeric phospho-tau in both, N2a and CTX culture
	- prevention of I2PP2A phosphorylation at Ser9 in neurons and animal models
.	- ATP-competitive CK2 inhibitor (IC50 = 130 nM)	Li et al. (2011); Ławnicka et al. (2010); Pagano et al. (2008); Yde et al. (2007)
DMAT	- inhibition of PIM1-3, HIPK2-3, DYRK1-3, PKD1, and CDK2 (IC50 values between 0.07–3.7 µM)
	- possesses anti-neoplastic effect on the growth and hormonal activity of human adrenocortical carcinoma cell line (H295R) in vitro
	- able to induce cell death in antiestrogen-resistant human breast cancer cells
	- inhibition of TDP-43 phosphorylation which is necessary for the decrease of the ND251 or ND207 aggregation
.	- orally bioavailable, highly selective, and potent CK2 inhibitor (IC50 value of 13 nM against CK2α and CK2α')	Buontempo et al. (2016); Chon et al. (2015); Cozza et al. (2012); Lee et al. (2019); Kim et al. (2014); Pierre et al. (2011); Rosenberger et al. (2016); Siddiqui-Jain et al. (2010);
Simitasertib (CX4945)	- in cancer cells, causes cell-cycle arrest and selectively induces apoptosis when compared to normal cells.
	- correlation between the antiproliferative activity and the expression of CK2α as well as inhibition of the PI3K/Akt signaling
	- synergistic effects on cell death in combination with other inhibitors
	- synergistic cytotoxic effects of bortezomib (20S proteasome inhibitor with Ki of 0.6 nM) and CX-4945 in acute lymphoblastic leukemia resulting in turning off the prosurvival ER chaperone BIP/Grp78 and turning on the pro-apoptotic NF-κB
	- dose-dependent inhibition of the IL-1β/TNF-α induced secretion of the inflammatory cytokines MCP-1 and IL-6 in human primary astrocytes and U373 astrocytoma cells
	- strong inhibition of CLK activity
	- inhibition of CDC2-like kinases in nanomolar range leading to the inhibition of the phosphorylation of serine/arginine-rich proteins in mammalian cells
	- induction of abnormal alternative splicing of CK2α′ pre-mRNA
	- orphan drug status by the US FDA for therapy of hard-to-treat bile duct cancers, known as cholangiocarcinomas
	- first described orally bioavailable CK2 inhibitor that advanced into clinical trials
. TTP22	- inhibition of CK2 with a Ki of 40 nM- high selectivity towards CK2 confirmed using serine/threonine (ASK1, JNK3, Aurora A, and Rock 1) and tyrosine protein kinases (FGFR1, Met, and Tie2)- inhibition of CK2 decreases taspase1-dependent MLL1 processing leading to higher MLL1 stability, and finally displace the MLL chimeras from chromatin- suppression of CK2 retard the leukemic progression in a MLL-AF9 leukemia mouse model	Golub et al. (2011); Zhao et al. (2018)
. SGC-CK2-1	- potent inhibitor of CK2 with activity on both isoforms, CK2α and CK2α’ (IC50 values of 4.2 nM and 2.3 nM, respectively)- inhibition of DYRK2 (IC50 of 440 nM)- potent suppression of CK2-mediated neuroinflammatory response inhibiting the expression of the proinflammatory cytokines IL-6 and IL-1β	Wells et al. (2021); Mishra et al. (2022)
. GO289	- potent and selective inhibitor of CK2 (IC50 of 7 nM) and minor effects on CK1δ and CK1α activities- inhibition of PIM2 (IC50 of 13 nM)- inhibition of the phosphorylation of clock proteins, including PER2- cell type-dependent inhibition of cancer cell growth that correlated with cellular clock function- in vitro potency and selectivity comparable to CX4945	Borgo et al. (2021b); Oshima et al. (2019)
.	- potent and selective dual inhibitor of CK2 and serine-arginine protein kinase 1 (SRPK1)	Dalle Vedove et al. (2020); Morooka et al. (2015)
SRPIN803-rev	- activity in mouse model of age-related macular degeneration due to the involvement of SRPK1 in angiogenesis and CK2 in neovascularization
. Compound 4	- the most potent SRPIN803-rev derivative (IC50 = 0.28 μM)- significant selectivity when tested on 320 kinases (inhibits only CK2 catalytic subunits by more than 50% at 1 μM concentration)- good cell permeability, inhibiting endocellularly CK2- significant reduction of Jurkat and CEM cells viability	Dalle Vedove et al. (2020)
.	- antioxidant, anti-cancer, and anti-inflammatory activities	Caltagirone et al. (2015); Daily et al. (2021); Guo et al. (2013); Kang et al. (2004); Kotanidou et al. (2002); Kwon, (2017); Lolli et al. (2012); Lopez-Lazaro, (2009); Rezai-Zadeh et al. (2009); Sharma et al. (2007)
Luteolin	- ATP-competitive inhibition of CK1 (IC50 = 1.6 μM)
	- inhibition of CK2 holoenzyme and CK2α (IC50 0.5 and 0.35 μM, respectively)
	- prevention of NDDs by reducing oxidative stress, inflammation, and Aβ production
	- protection against lipopolysaccharide-induced lethal toxicity and a reduction of the expression of pro-inflammatory intermediate in mice (0.2 mg/kg)
	- reduction of 6-hydroxy-dopamine-derived toxicity leading to neuroprotection in rat pheochromocytoma PC12 cells (3.13–50 μM)
	- neuroprotective effects on stroke patients undergoing neurorehabilitation as a component of a co-ultramicronized composite (140 mg/day for 60 days) and palmitoylethanolamine
	- improvement of brain insulin resistance as well as inflammation protecting against the development of AD and the gut microbiota-liver-brain axis
. Quercetin	- antioxidant and anti-inflammatory activities- potent inhibition of all CK2 isoforms with IC50 values below 1 µM- affects ROS-producing enzymes and protects neurons from oxidative stress-induced damage- potential up- and/or down-regulation of cytokines via Nrf2, ERK1/2, PI3K/Akt, JNK, MAPK pathways- Improvement of cognitive performance and cognitive functions in patients with neurological diseases or neurobehavioral disorders- inhibition of Aβ production in vitro and protection against cognitive impairments in a mouse model	Baier et al. (2018); Nakagawa and Ohta, (2019); Selvakumar et al. (2012); Zaplatic et al. (2019)
. Chrysoeriol	- inhibition with IC50 values in low nanomolar range- administration alleviates the damage caused by cerebral ischemia and reperfusion in MCAO model rats- administration reduces the area of brain infarction and relief of neurobehavioral deficits- inhibition of the production of pro-inflammatory cytokines,- reduction of neuronal apoptosis and promotion of nerve growth- neuroprotective mechanism is strongly linked to the activation of the Wnt/β-catenin signaling pathway	Baier et al. (2017); Shao et al. (2021)
.	- potent, selective, ATP-competitive, and cell-permeable inhibitor of CK2 ( Ki = 50 nM)	Cozza et al. (2009); Cozza et al. 2015; Schwind et al. (2017); Zhou et al. (2015)
Quinalizarin	- able to discriminate between the free catalytic subunits and the CK2 holoenzymes
	- downregulation of transcription factors and modulation of microRNA in 3T3-L1 cells leading to inhibition of adipogenesis
	- inhibition of cell viability, especially in adenocarcinoma cells harboring EGFR sensitive mutation and interruption of migration
	- stimulation of apoptosis in different human lung cancer cell lines
. Bikaverin	- moderate ATP-directed inhibitor of the CK2 holoenzyme (IC50 of 1.24 µM)- reduction of cell viability and proliferation in cancer cell lines, like MCF7, A427, and A431 (10 μM)TTBK1/2 inhibitors- cytotoxic and antitumor effect on L5178Y lymphoma cells (IC50 of 0.23 μg/ml) and on BALB/c mice inoculated with L5178Y- capable to recover the nuclear and mitochondrial integrity in H2O2-induced damaged cells	Haidar et al. (2019); Nirmaladevi et al. (2014); Hinojosa-Ventura et al. (2019)
. Resveratrol	- antioxidant, anti-cancer, anti-inflammatory, and anti-aging properties- CNS penetrating molecule- increases the activity of antioxidant enzymes- reduction of the cell viability of human breast carcinoma cells (MCF-7) dependent on the concentration (IC50 = 106 μM)- inhibition of CK2 activity by 1.6-fold- decrease of the potential of the mitochondrial membrane- increases ROS levels by 1.7-fold- protection of the central nervous system against symptoms of disorders, like stroke, spinal cord injury-induced inflammation, AD, PD, or HD- activation of SIRT1, Nrf2, and AMP-activated kinase	Ahmed et al. (2017); Costa et al. (2021); Gomes et al. (2018); Farkhondeh et al. (2020); Kim et al. (2018); Komorowska et al. (2020); Kumar et al. (2011); Turner et al. (2015); Liu et al. (2015); Zhao et al. (2021); Maher et al. (2010); Yu et al. (2016); Su et al. (2021); Yang et al. (2021)
.	- potent ATP-competitive CK2 inhibitor (IC50 = 40 nM, Ki = 20 nM)	Baluchnejadmojarad et al. (2017); Cozza et al. (2006); Dheen et al. (2005); Ebrahimi et al. (2019); Lastres-Becker et al. (2016); Liu et al. (2017); Ríos et al. (2018); Vargas et al. (2006); Wang et al. (1998); Wei et al. (2020)
Ellagic acid	- inhibitory effects towards the activity of many kinases such as LYN, PKA, SYK, GSK3, PKC, FGR, or CK1 (IC50 values between 2.9 and 13 µM)
	- normalization of the lipid metabolism and the lipidemic profile
	- regulation of proinflammatory mediators, such as IL-6, IL-1β, and TNF-α
	- upregulation of Nrf2 and the inhibition NF-κB
	- neuroprotection due to antioxidant properties, ability to iron chelating, the induction of signaling pathways, and the reduction of mitochondrial dysfunction
	- neuroprotective contribution towards several neurotoxins in numerous animal models
	- neuroprotective effect in the 6-OHDA rat model of PD (50 mg/kg/day for one week)
	- neuroprotective potential by the reduction of apoptosis and oxidative stress, and inhibition of MAO-B.
	- effect on the ERβ/Nrf2/HO-1 signaling cascade
	- protective influence on DA neurons from rotenone-induced neuronal damage by activating Nrf2 signaling
	- induction of Nrf2 and HO-1 expression and inhibition of the NF-κB signaling pathway
	- protection of rats (6-OHDA rat model) against MTX-induced apoptosis and mitochondrial dysfunction
	- significant reduction of the volume of cerebrum infarction and the neurological deficit scores of the rats in an experimental rat model based on oxygen-glucose deprivation and reoxygenation in primary cultured cortical rat neurons.
	- increase of the number of Bcl-2-positive cells and the ratio of Bcl-2-positive to Bax-positive neurons in the semidarkness zone near the brain ischemic focus in the photothrombotic cerebral ischemia model
	- higher neuron viability, cell nuclear integrity, and a higher ratio of Bcl-2/Bax expression in the primary cultured neuron model
	- decrease of the number of apoptotic cells

Inhibitors of CK1, TTBK, and CK2.

The development of specific CK1 inhibitors capable to cross the blood-brain-barrier is a promising target for the treatment of TDP-43 proteinopathies, e.g., ALS. Small brain-penetrating molecules were described which block the neurotoxicity of TDP-43 in cell culture experiments through inhibition of its phosphorylation (Perez et al., 2011; Salado et al., 2014; Morales-Garcia et al., 2017). Up to now, few CK1-specific compounds have been synthesised and a small part of them has been also examined in animal models. Kinetic studies of these compounds revealed an ATP-competitive mode of action in the case of almost all molecules.

In several studies, it has been proven that CK1 activity is necessary for molecular pacemaking. It was shown that CK1δ is the main regulatory element of the clock period: inhibition of CK1δ remarkably prolongated the circadian rhythms in locomotor activity in vivo and molecular oscillations in the suprachiasmatic nucleus (SCN) and peripheral tissue slices in vitro. Additionally, cumulation of PER2 protein in the nucleus was observed, in vitro and in vivo (Meng et al., 2010).

Cell proliferation is increased and colony formation is promoted through overexpression of CK1α. Effects of CK1α inhibition include the increase of the sensitivity to radiotherapy and reduction of the production and secretion of pro-inflammatory factors (Liu et al., 2021).

Several benzimidazole-based inhibitors displayed significant inhibition of CK1δ, e.g., Bischof-5 and -6. Other potent ATP-competitive and selective CK1δ/ε inhibitors are represented by difluoro-dioxolo-benzimidazole derivatives, compounds 1 and 2 (Richter et al., 2014). Substances derived from inhibitors of Wnt production (IWP) are structurally similar to benzimidazoles. Such inhibitors have been characterized as ATP-competitive and CK1 specific.

Another potent inhibitor, compound 1h, which is highly selective and CK1 isoform-specific was identified from a high-throughput screen of the Amgen compound library (Hua et al., 2012).

Many modulators of CK1 presently under investigation are isolated from natural environment or are derivatives of natural products. Nowadays, compounds from marine organisms are getting more attention and are now being investigated in clinical tests, essentially against cancer, inflammation, chronic pain, and NDDs. Among the promising drug candidates is the family of lamellarins, which are marine alkaloids with fused 14-phenyl-6H-[1]benzopyrano[4′,3′:4,5]pyrrolo[2,1-a]isoquinoline or non-fused 3,4-diarylpyrrole-2-carboxylate ring systems (Baunbæk et al., 2008; Bailly, 2015; Fukuda et al., 2020). So far, over 50 lamellarins have been purified from different marine organisms, e.g., mollusks, tunicates, and sponges. In 2008, protein kinases have been identified as new molecular targets of anticancer lamellarins (Baunbæk et al., 2008). 22 lamellarins were screened for cancer- and Alzheimer’s disease-relevant protein kinases.

Until now, only a few protein kinases were described, which are associated with abnormal TDP-43 hyperphosphorylation, including both TTBK isoforms (Versluys et al., 2022). Both are known to colocalize with TDP-43 inclusions in spinal cords of ALS patients. TTBK2 is involved in crucial cellular mechanisms, e.g., ciliogenesis, microtubule dynamics, and neurotransmitter trafficking. Thus, its reduced activty may have negative effects for the patients (Jackson, 2012; Bowie and Goetz, 2020). Only a small number of TTBK1/2 inhibitors have been described, but unfortunately they do not show selectivity for one isoform (Xue et al., 2013; Kiefer et al., 2014).

A set of TTBK1 azaindazole inhibitors has been examined (Halkina et al., 2021). Two of them are characterized by high potency, selectivity and they are brain penetrant: compound 8 (4-(1-(2-Aminopyrimidin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-2- methylbut-3-yn-2-ol) with an IC₅₀ of 60 nM and compound 31 ((S)-1-(1-(2-Amino-6-methoxypyrimidin-4-yl)-1H-pyrrolo[3,2-c]-pyridin-6-yl)-3-methylpent-1-yn-3-ol) with an IC₅₀ of 2.7 nM.

Lately, receptor-based pharmacophore models were developed applying three TTBK1 protein structures. The combination of integrated e-pharmacophore based virtual screening and molecular dynamics simulation resulted in four hits: ZINC14644839 (5,6,4′-Trihydroxy-7,3′-Dimethoxyflavone, 5-TDMF), ZINC00012956 (3-phenyl-2-(9H-purin-6-ylamino)propan-1-ol), ZINC91332506 (1-[3-(6-aminopurin-9-yl)propyl]-3-methyl-pyridin-2-one), and ZINC69775110 (N-[(4-ethoxy-3-fluoro-phenyl)methyl]-7H-purin-6-amine). AMG-28 (4-(2-amino-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cyclohepta[1,2-b]indol-11-yl)-2-methylbut-3-yn-2-ol) was originally designed as an inhibitor of a Ser/Thr protein kinase essential for the activation of the NF-κB pathway (NIK) (Li et al., 2013). A co-crystal structure of this inhibitor with the kinase domain of human TTBK1 showed binding of the aminopyrimidine ring with the hinge region of protein kinase. On the basis of AMG-28 11 new indolyl pyriminidine compounds were synthetized. New analogs are more potent inhibitors of TTBK2 than TTBK1 (Potjewyd et al., 2022).

Compounds that may inhibit CK2 activities where described in numerous publications. Since research results on the role of CK2 in NDD are diverse, there are only a few reports about CK2 inhibitors on NDDs available. The observation that CK2 is either overactive or overexpressed in patient brains supports kinase inhibition as a therapeutic approach for multiple neurodegenerative diseases. A large group of CK2 inhibitors, known for more than 20 years, are benzimidazoles, e.g., TBB and DMAT (Szyszka et al., 1995).

Data propose the influence of CK2 on astrocytes in the neuroinflammatory response in AD. In astrocytes in the hippocampus and temporal cortex of AD patients levels of CK2α/α’ are increased. Those astrocytes are linked to amyloid deposits in the AD brain. In human primary astrocytes and U373 astrocytoma cells, the IL-1β/TNF-α induced secretion of the inflammatory cytokines MCP-1 and IL-6 is potently inhibited by CX-4945 dependent on the dose (Rosenberger et al., 2016). CX-4945 is the first described orally bioavailable CK2 inhibitor that advanced into clinical trials (Pierre et al., 2011; Cozza et al., 2012).

Quite recently SRPIN803-rev (6-(4-hydroxy-3-metoxybenzylidene)-5-imino-2-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7(6H)-one), a new dual inhibitor of CK2 and serine-arginine protein kinase 1, was identified (Dalle Vedove et al., 2020). SRPIN803-rev and its new synthesized derivatives bind to the open conformation of the hinge/αD region within the ATP-binding pocket of CK2α.

The MLL/COMPASS stability is regulated by taspase1 cleavage and might be a possible target for clinical therapy of leukemia. Destabilized MLL and unprocessed version MLL1 associated with chromatin results in the displacement of MLL chimeras from chromatin in leukemic cells. The CK2 phosphorylation site is next to the taspase1 cleavage site, and enables its cleavage. Inhibition of CK2 by specific inhibitors (CX-4945 or TTP22) decrease taspase1-dependent MLL1 processing, which leads to higher MLL1 stability, and finally displace the MLL chimeras from chromatin. In a MLL-AF9 leukemia mouse model the suppression of CK2 retard the leukemic progression (Zhao et al., 2018).

Naturally occurring compounds might act as antioxidant, anti-inflammatory, antiviral, antimicrobial, and anticancer agents (Baier and Szyszka, 2020). They have shown neuroprotective effects in many clinical trials (Ullah et al., 2020; Akter et al., 2021; Kim and Park, 2021; Wang et al., 2021).

It has been proven that flavonoids are most effective in the treatment of NDDs, including AD. First analyses with flavonoids against CK2 were reported by Li et al. (2009), Lolli et al. (2012). As we described in our own publications, flavonoids naturally occurring in plants are highly potent CK2 inhibitors. A set of more than 20 compounds (e.g., apigenin, pedalitin, and chrysoeriol) was tested for their inhibitory effect on four human CK2 isoforms. The results reveal that CK2α’ was most sensitive to the examined compounds (Baier et al., 2017; Baier et al., 2018).

Quercetin (3,5,7,3′,4′–pentahydroxyflavone) belongs to the polyphenolic compounds with powerful antioxidant and anti-inflammatory activities. Polyphenolic compounds are often applied in the treatment and protection against severe diseases, like diabetes, cancer, neurodegenerative and cardiovascular diseases.

In time-course experiments it was shown that CK2 is crucial at early time points just after the induction of cell differentiation (Schwind et al., 2017).

In several studies it was observed that Nrf2 signaling is involved in PD pathogenesis (Dheen et al., 2005). The increase of Nrf2 induced dopamine (DA) neuroprotection and, at the same time, the decrease of Nrf2 altered DA neurons to get sensitive to oxidative stress damage (Lastres-Becker et al., 2016). It was shown that the progress of PD is linked to an incomplete activation of Nrf2 (Vargas et al., 2006).

Conclusion

During past decades many research groups provided new information to better understand the molecular aspects of cancerogenesis and neurodegenerative diseases. Protein kinases play an important role in the regulation of the activity of a huge amount of proteins involved in the control of different cell functions. Nevertheless, in many cases of NDDs, protein aggregation often caused by (hyper-)phosphorylation is observed. Therefore, the inhibition of these reactions is a promising therapeutic target. Unfortunately, whereas for the treatment of cancers several compounds were successfully developed, there does not exist a therapy for NDDs being a kinase inhibitor. Until September 2021, 73 small molecule kinase inhibitors were approved by FDA but only a small amount of them are for noncancer-related diseases (Ayala-Aguilera et al., 2022). The main obstacle in the design of substances targeting the CNS is the effective crossing of the blood-brain-barrier which is necessary in the treatment of NDDs, but also in the case of oncology. CK1 superfamily and CK2 play essential roles in the regulation of cell processes, like in signaling pathways. With respect to this fact, it is not surprising that their deregulation might be associated to numerous disorders, e.g., inflammations, cancer, and NDDs. The starting point for CK1 inhibitors could be described as poorly selective and weakly potent molecules necessary to be improved for application in pharmacological treatment. Subsequently, compounds were developed, which show significant preference between the functionally different CK1 isoforms. Noteworthy, Pfizer designed two ATP-competitive compounds (PF-4800567 and PF-0670462), which possess selectivity towards the CK1δ and CK1ε isoforms. TG Therapeutics discovered umbralisib (UKONIQ™), an orally available dual inhibitor for PI3Kδ and CK1ε applied in the treatment of adults with relapsed or refractory marginal zone lymphoma, which received its FDA approval in 2021 (Burris et al., 2018). Despite this, there are no CK1 inhibitors reaching the clinical stage in neurodegenerative disorders. Those first successes raise the hope for the design of more selective and potent inhibitors of CK1 isoforms to improve the therapeutic opportunities.

In the case of TTBK1/2, up to date, only a small amount of molecules are known, which show potent inhibitory activity towards TTBK1/2. The undisputable advantage of TTBK1 over other kinases is its specific expression in neurons, and therefore, it seems to be a favorable target for NDDs.

Many kinds of CK2 inhibitors have been reported by using different methods, e.g., computer-aided drug design or structure-based reconstitution. Most of them lack cell permeability, high selectivity, but possess off-target potential. The latter might be explained by the fact that this kinase phosphorylates a huge amount of protein substrates. The principle characteristics for a satisfactory molecule are, furthermore, metabolic stability and a good pharmacokinetic profile. Even the best compound CX-4945, already in clinical use, is not devoid of unspecific effects. Nevertheless, the number of newly developed inhibitors (GO289, SGC-CK2-1, and the SRPIN803-rev derivatives), may increase the chance of developing highly selective and CNS penetrating molecules for CK2 in the near future.

References

• 1

  AckermannK.NeidhartT.GerberJ.WaxmannA.PyerinW. (2005). The catalytic subunit α′ gene of human protein kinase CK2 (CSNK2A2): Genomic organization, promoter identification and determination of Ets1 as a key regulator. Mol. Cell. Biochem.274, 91–101. 10.1007/s11010-005-3076-2

  • CrossRef
  • Google Scholar

• 2

  AdlerP.MayneJ.WalkerK.NingZ.FigeysD. (2019). Therapeutic targeting of casein kinase 1δ/ε in an Alzheimer’s disease mouse model. J. Proteome Res.18, 3383–3393. 10.1021/acs.jproteome.9b00312

  • CrossRef
  • Google Scholar

• 3

  AhmedT.JavedS.JavedS.TariqA.ŠamecD.TejadaS.et al (2017). Resveratrol and Alzheimer’s disease: Mechanistic insights. Mol. Neurobiol.54, 2622–2635. 10.1007/s12035-016-9839-9

  • CrossRef
  • Google Scholar

• 4

  AkterR.RahmanH.BehlT.ChowdhuryM. A. R.ManirujjamanM.BulbulI. J.et al (2021). Prospective role of polyphenolic compounds in the treatment of neurodegenerative diseases. CNS Neurol. Disord. Drug Targets20, 430–450. 10.2174/1871527320666210218084444

  • CrossRef
  • Google Scholar

• 5

  AlquezarC.SaladoI. G.de la EncarnaciónA.PérezD. I.MorenoF.GilC.et al (2016). Targeting TDP-43 phosphorylation by casein kinase-1δ inhibitors: A novel strategy for the treatment of frontotemporal dementia. Mol. Neurodegener.11, 36. 10.1186/s13024-016-0102-7

  • CrossRef
  • Google Scholar

• 6

  AndrewS. E.GoldbergY. P.KremerB.TeleniusH.TheilmannJ.AdamS.et al (1993). The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington’s disease. Nat. Genet.4, 398–403. 10.1038/ng0893-398

  • CrossRef
  • Google Scholar

• 7

  AraiT.HasegawaM.AkiyamaH.IkedaK.NonakaT.MoriH.et al (2006). TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun.351, 602–611. 10.1016/j.bbrc.2006.10.093

  • CrossRef
  • Google Scholar

• 8

  ArditoF.GiulianiM.PerroneD.TroianoG.MuzioL. L. (2017). The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review). Int. J. Mol. Med.40, 271–280. 10.3892/ijmm.2017.3036

  • CrossRef
  • Google Scholar

• 9

  ArenasJ.CamposY.RibacobaR.MartínM. A.RubioJ. C.AblanedoP.et al (1998). Complex I defect in muscle from patients with Huntington’s disease. Ann. Neurol.43, 397–400. 10.1002/ana.410430321

  • CrossRef
  • Google Scholar

• 10

  AtwalR. S.DesmondC. R.CaronN.MaiuriT.XiaJ.SipioneS.et al (2011). Kinase inhibitors modulate huntingtin cell localization and toxicity. Nat. Chem. Biol.7, 453–460. 10.1038/nchembio.582

  • CrossRef
  • Google Scholar

• 11

  AugustinackJ. C.SchneiderA.MandelkowE. M.HymanB. T. (2002). Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. Acta Neuropathol.103, 26–35. 10.1007/s004010100423

  • CrossRef
  • Google Scholar

• 12

  AvrahamE.RottR.LianiE.SzargelR.EngelenderS. (2007). Phosphorylation of parkin by the cyclin-dependent kinase 5 at the linker region modulates its ubiquitin-ligase activity and aggregation. J. Biol. Chem.282, 12842–12850. 10.1074/jbc.M608243200

  • CrossRef
  • Google Scholar

• 13

  AyalaY. M.ZagoP.D’AmbrogioA.XuY.-F.PetrucelliL.BurattiE.et al (2008). Structural determinants of the cellular localization and shuttling of TDP-43. J. Cell Sci.121, 3778–3785. 10.1242/jcs.038950

  • CrossRef
  • Google Scholar

• 14

  Ayala-AguileraC. C.ValeroT.lvaro Lorente-MacíasÁ.BaillacheD. J.CrokeS.Unciti-BrocetaA. (2022). Small molecule kinase inhibitor drugs (1995–2021): Medical indication, pharmacology, and synthesis. J. Med. Chem.65, 1047–1131. 10.1021/acs.jmedchem.1c00963

  • CrossRef
  • Google Scholar

• 15

  AzizN. A.van der BurgJ. M. M.LandwehrmeyerG. B.BrundinP.StijnenT.EHDI Study Groupet al (2008). Weight loss in Huntington disease increases with higher CAG repeat number. Neurology71, 1506–1513. 10.1212/01.wnl.0000334276.09729.0e

  • CrossRef
  • Google Scholar

• 16

  BaduraL.SwansonT.AdamowiczW.AdamsJ.CianfrognaJ.FisherK.et al (2007). An inhibitor of casein kinase I induces phase delays in circadian rhythms under free-running and entrained conditions. J. Pharmacol. Exp. Ther.322, 730–738. 10.1124/jpet.107.122846

  • CrossRef
  • Google Scholar

• 17

  BaierA.GalickaA.NazarukJ.SzyszkaR. (2017). Selected flavonoid compounds as promising inhibitors of protein kinase CK2α and CK2α’, the catalytic subunits of CK2. Phytochemistry136, 39–45. 10.1016/j.phytochem.2016.12.018

  • CrossRef
  • Google Scholar

• 18

  BaierA.NazarukJ.GalickaA.SzyszkaR. (2018). Inhibitory influence of natural flavonoids on human protein kinase CK2 isoforms: Effect of the regulatory subunit. Mol. Cell. Biochem.444, 35–42. 10.1007/s11010-017-3228-1

  • CrossRef
  • Google Scholar

• 19

  BaierA.SzyszkaR. (2020). Compounds from natural sources as protein kinase inhibitors. Biomolecules10 (11), 1546. 10.3390/biom10111546

  • CrossRef
  • Google Scholar

• 20

  BaillyC. (2015). Anticancer properties of lamellarins. Mar. Drugs13, 1105–1123. 10.3390/md13031105

  • CrossRef
  • Google Scholar

• 21

  BainJ.PlaterL.ElliottM.ShpiroN.HastieC. J.McLauchlanH.et al (2007). The selectivity of protein kinase inhibitors: A further update. Biochem. J.408, 297–315. 10.1042/BJ20070797

  • CrossRef
  • Google Scholar

• 22

  BallB. J.SteinA. S.BorthakurG.MurrayC.KookK.ChanK. W. H.et al (2020). Trial in progress: A phase I trial of BTX-A51 in patients with relapsed or refractory aml or high-risk mds. Blood136, 18–19. 10.1182/blood-2020-142557

  • CrossRef
  • Google Scholar

• 23

  BaluchnejadmojaradT.RabieeN.ZabihnejadS.RoghaniM. (2017). Ellagic acid exerts protective effect in intrastriatal 6-hydroxydopamine rat model of Parkinson’s disease: Possible involvement of ERβ/Nrf2/HO-1 signaling. Brain Res.1662, 23–30. 10.1016/j.brainres.2017.02.021

  • CrossRef
  • Google Scholar

• 24

  BaoC.BajramiB.MarcotteD. J.ChodaparambilJ. V.KernsH. M.HendersonJ.et al (2021). Mechanisms of regulation and diverse activities of tau-tubulin kinase (TTBK) isoforms. Cell. Mol. Neurobiol.41, 669–685. 10.1007/s10571-020-00875-6

  • CrossRef
  • Google Scholar

• 25

  BarmadaS. J.SkibinskiG.KorbE.RaoE. J.WuJ. Y.FinkbeinerS. (2010). Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis. J. Neurosci.30, 639–649. 10.1523/jneurosci.4988-09.2010

  • CrossRef
  • Google Scholar

• 26

  BaunbækD.TrinklerN.FerandinY.LozachO.PloypradithP.RucirawatS.et al (2008). Anticancer alkaloid lamellarins inhibit protein kinases. Mar. Drugs6, 514–527. 10.3390/md20080026

  • CrossRef
  • Google Scholar

• 27

  BennC. L.DawsonL. A. (2020). Clinically precedented protein kinases: Rationale for their use in neurodegenerative disease. Front. Aging Neurosci.12, 242. 10.3389/fnagi.2020.00242

  • CrossRef
  • Google Scholar

• 28

  BibianM.RahaimR. J.ChoiJ. Y.NoguchiY.SchürerS.ChenW.et al (2013). Development of highly selective casein kinase 1δ/1ε (CK1δ/ε) inhibitors with potent antiproliferative properties. Bioorg. Med. Chem. Lett.23, 4374–4380. 10.1016/j.bmcl.2013.05.075

  • CrossRef
  • Google Scholar

• 29

  BichelmeierU.SchmidtT.HübenerJ.BoyJ.RüttigerL.HäbigK.et al (2007). Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3: In vivo evidence. J. Neurosci.27, 7418–7428. 10.1523/JNEUROSCI.4540-06.2007

  • CrossRef
  • Google Scholar

• 30

  BinderL. I.FrankfurterA.RebhunL. I. (1985). The distribution of tau in the mammalian central nervous system. J. Cell Biol.101, 1371–1378. 10.1083/jcb.101.4.1371

  • CrossRef
  • Google Scholar

• 31

  BinghamE. W.FarrelH. M.Jr. (1974). Casein kinase from the Golgi apparatus of lactating mam mary gland. J. Biol. Chem.249, 3647–3651. 10.1016/S0021-9258(19)42622-7

  • CrossRef
  • Google Scholar

• 32

  BischofJ.LebanJ.ZajaM.GrotheyA.RadunskyB.OthersenO.et al (2012). 2-Benzamido-N-(1H-benzo[d]imidazol-2-yl)thiazole-4-carboxamide derivatives as potent ihnhibitors CK1δ/ε. Amino Acids43, 1577–1591. 10.1007/s00726-012-1234-x

  • CrossRef
  • Google Scholar

• 33

  BlanquetP. R. (2000). Casein kinase 2 as a potentially important enzyme in the nervous system. Prog. Neurobiol.60, 211–246. 10.1016/s0301-0082(99)00026-x

  • CrossRef
  • Google Scholar

• 34

  BorgoC.CesaroL.HirotaT.KuwataK.D’AmoreC.RuppertT.et al (2021a). Comparing the efficacy and selectivity of CK2 inhibitors. A phosphoproteomics approach. Eur. J. Med. Chem.214, 113217. 10.1016/j.ejmech.2021.113217

  • CrossRef
  • Google Scholar

• 35

  BorgoC.D’AmoreC.SarnoS.SalviM.RuzzeneM. (2021b). Protein kinase CK2: A potential therapeutic target for diverse human diseases. Signal Transduct. Target. Ther.6, 183. 10.1038/s41392-021-00567-7

  • CrossRef
  • Google Scholar

• 36

  BouskilaM.EsoofN.GayL.FangE. H.DeakM.BegleyM. J.et al (2011). TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development. Biochem. J.437, 157–167. 10.1042/bj20110276

  • CrossRef
  • Google Scholar

• 37

  BowieE.GoetzS. C. (2020). TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons. Elife9, e51166. 10.7554/eLife.51166

  • CrossRef
  • Google Scholar

• 38

  BoyarkoB.HookV. (2021). Human tau isoforms and proteolysis for production of toxic tau fragments in neurodegeneration. Front. Neurosci.15, 702788. 10.3389/fnins.2021.702788

  • CrossRef
  • Google Scholar

• 39

  BraakH.BraakE. (1991). Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol.82, 239–259. 10.1007/BF00308809

  • CrossRef
  • Google Scholar

• 40

  BragginJ. E.BucksS. A.CourseM. M.SmithC. L.SopherB.OsnisL.et al (2019). Alternative splicing in a presenilin 2 variant associated with Alzheimer disease. Ann. Clin. Transl. Neurol.6, 762–777. 10.1002/acn3.755

  • CrossRef
  • Google Scholar

• 41

  BuontempoF.OrsiniE.LonettiA.CapelliniA.ChiariniF.EvangelistiC.et al (2016). Synergistic cytotoxic effects of bortezomib and CK2 inhibitor CX-4945 in acute lymphoblastic leukemia: Turning off the prosurvival ER chaperone BIP/Grp78 and turning on the pro-apoptotic NF-κB. Oncotarget7, 1323–1340. 10.18632/oncotarget.6361

  • CrossRef
  • Google Scholar

• 42

  BurnettB.LiF.PittmanR. N. (2003). The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity. Hum. Mol. Genet.12, 3195–3205. 10.1093/hmg/ddg344

  • CrossRef
  • Google Scholar

• 43

  BurnettG.KennedyE. P. (1954). The enzymatic phosphorylation of proteins. J. Biol. Chem.211, 969–980. 10.1016/S0021-9258(18)71184-8

  • CrossRef
  • Google Scholar

• 44

  BurréJ.SharmaM.SüdhofT. C. (2018). Cell biology and pathophysiology of α-synuclein. Cold Spring Harb. Perspect. Med.8, a024091. 10.1101/cshperspect.a024091

  • CrossRef
  • Google Scholar

• 45

  BurrisH. A.FlinnI. W.PatelM. R.FenskeT. S.DengC.BranderD. M.et al (2018). Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: An open-label, phase 1, dose-escalation, first-in-human study. Lancet. Oncol.19, 486–496. 10.1016/s1470-2045(18)30082-2

  • CrossRef
  • Google Scholar

• 46

  BurzioV.AntonelliM.AllendeC. C.AllendeJ. E. (2002). Biochemical and cellular characteristics of the four splice variants of protein kinase CK1alpha from zebrafish (Danio rerio). J. Cell. Biochem.86, 805–814. 10.1002/jcb.10263

  • CrossRef
  • Google Scholar

• 47

  CaltagironeC.CisariC.SchievanoC.Di PaolaR.CordaroM.BruschettaG.et al (2015). Co-Ultramicronized palmitoylethanolamide/luteolin in the treatment of cerebral ischemia: From rodent to man. Transl. Stroke Res.7, 54–69. 10.1007/s12975-015-0440-8

  • CrossRef
  • Google Scholar

• 48

  CarterB.JustinH. S.GulickD.GamsbyJ. J. (2021). The molecular clock and neurodegenerative disease: A stressful time. Front. Mol. Biosci.8, 644747. 10.3389/fmolb.2021.644747

  • CrossRef
  • Google Scholar

• 49

  CastelloJ.RagnauthA.FriedmanE.RebholzH. (2017). CK2—an emerging target for neurological and psychiatric disorders. Pharmaceuticals10, 7. 10.3390/ph10010007

  • CrossRef
  • Google Scholar

• 50

  ChakrabortyJ.BassoV.ZivianiE. (2017). Post translational modification of Parkin. Biol. Direct12, 6. 10.1186/s13062-017-0176-3

  • CrossRef
  • Google Scholar

• 51

  ChenC.GuJ.Basurto-IslasG.JinN.WuF.GongC.-X.et al (2017). Up-regulation of casein kinase 1ε is involved in tau pathogenesis in Alzheimer’s disease. Sci. Rep.7, 13478. 10.1038/s41598-017-13791-5

  • CrossRef
  • Google Scholar

• 52

  ChenG.-F.XuT.-H.YanY.ZhouY.-R.JiangY.MelcherK.et al (2017). Amyloid beta: Structure, biology and structure-based therapeutic development. Acta Pharmacol. Sin.38, 1205–1235. 10.1038/aps.2017.28

  • CrossRef
  • Google Scholar

• 53

  CheongJ. K.HungN. T.WangH.TanP.VoorhoeveP. M.LeeS. H.et al (2011). IC261 induces cell cycle arrest and apoptosis of human cancer cells via CK1δ/ɛ and Wnt/β-catenin independent inhibition of mitotic spindle formation. Oncogene30, 2558–2569. 10.1038/onc.2010.627

  • CrossRef
  • Google Scholar

• 54

  ChohanM. O.KhatoonS.IqbalI.-G.IqbalK. (2006). Involvement of I2PP2A in the abnormal hyperphosphorylation of tau and its reversal by Memantine. FEBS Lett.580, 3973–3979. 10.1016/j.febslet.2006.06.021

  • CrossRef
  • Google Scholar

• 55

  ChonH. J.BaeK. J.LeeY.KimJ. (2015). The casein kinase 2 inhibitor, CX-4945, as an anti-cancer drug in treatment of human hematological malignancies. Front. Pharmacol.6, 70. 10.3389/fphar.2015.00070

  • CrossRef
  • Google Scholar

• 56

  CitronM.DiehlT. S.GordonG.BiereA. L.SeubertP.SelkoeD. J. (1996). Evidence that the 42- and 40-amino acid forms of amyloid β protein are generated from the β-amyloid precursor protein by different protease activities. Proc. Natl. Acad. Sci. U. S. A.93, 13170–13175. 10.1073/pnas.93.23.13170

  • CrossRef
  • Google Scholar

• 57

  CohenP. (2002). The origins of protein phosphorylation. Nat. Cell Biol.4, E127–E130. 10.1038/ncb0502-e127

  • CrossRef
  • Google Scholar

• 58

  ConwayK. A.HarperJ. D.LansburyP. T. (1998). Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat. Med.4, 1318–1320. 10.1038/3311

  • CrossRef
  • Google Scholar

• 59

  CooksonM. R.LockhartP. J.McLendonC.O’FarrellC.SchlossmacherM.FarrerM. J. (2003). RING finger 1 mutations in parkin produce altered localization of the protein. Hum. Mol. Genet.12, 2957–2965. 10.1093/hmg/ddg328

  • CrossRef
  • Google Scholar

• 60

  CornettJ.CaoF.WangC. E.RossC. A.BatesG. P.LiS. H.et al (2005). Polyglutamine expansion of huntingtin impairs its nuclear export. Nat. Genet.37, 198–204. 10.1038/ng1503

  • CrossRef
  • Google Scholar

• 61

  CostaP. S. D.RamosP. S.FereiraC.SilvaJ. L.El-BahaT.FialhoE. (2021). Pro-oxidant efeect of resveratrol on human breast cancer MCF-7 cells is associated with CK2 inhibition. Nutr. Cancer14, 1–10. 10.1080/016355581.2021.1977834

  • CrossRef
  • Google Scholar

• 62

  CozzaG.BonviniP.ZorziE.PolettoG.PaganoM. A.SarnoS.et al (2006). Identification of ellagic acid as potent inhibitor of protein kinase CK2: A successful example of a virtual screening application. J. Med. Chem.49, 2363–2366. 10.1021/jm060112m

  • CrossRef
  • Google Scholar

• 63

  CozzaG.GianoncelliA.MontopoliM.CaparrottaL.VenerandoA.MeggioF.et al (2008). Identification of novel protein kinase CK1 delta (CK1delta) inhibitors through structure-based virtual screening. Bioorg. Med. Chem. Lett.18, 5672–5675. 10.1016/j.bmcl.2008.08.072

  • CrossRef
  • Google Scholar

• 64

  CozzaG.MazzoranaM.PapinuttoE.BainJ.ElliottM.di MairaG.et al (2009). Quinalizarin as a potent, selective and cell-permeable inhibitor of protein kinase CK2. Biochem. J.421, 387–395. 10.1042/bj20090069

  • CrossRef
  • Google Scholar

• 65

  CozzaG.PinnaL. A. (2016). Casein kinases as potential therapeutic targets. Expert Opin. Ther. Targets20, 319–340. 10.1517/14728222.2016.1091883

  • CrossRef
  • Google Scholar

• 66

  CozzaG.PinnaL. A.MoroS. (2012). Protein kinase CK2 inhibitors: A patent review. Expert Opin. Ther. Pat.22, 1081–1097. 10.1517/13543776.2012.717615

  • CrossRef
  • Google Scholar

• 67

  CozzaG.VenerandoA.SarnoS.PinnaL. A. (2015). The selectivity of CK2 inhibitor quinalizarin: A reevaluation. Biomed. Res. Int.2015, 734127. 10.1155/2015/734127

  • CrossRef
  • Google Scholar

• 68

  CunninghamP. S.AhernS. A.SmithL. C.da Silva SantosC. S.WagerT. T.BechtoldD. A. (2016). Targeting of the circadian clock via CK1δ/ε to improve glucose homeostasis in obesity. Sci. Rep.6, 29983. 10.1038/srep29983

  • CrossRef
  • Google Scholar

• 69

  DailyJ. W.KangS.ParkS. (2021). Protection against Alzheimer's disease by luteolin: Role of brain glucose regulation, anti-inflammatory activity, and the gut microbiota-liver-brain axis. Biofactors47, 218–231. 10.1002/biof.1703

  • CrossRef
  • Google Scholar

• 70

  Dalle VedoveA.ZontaF.ZanforlinE.DemitriN.RibaudoG.CazzanelliG.et al (2020). A novel class of selective CK2 inhibitors targeting its open hinge conformation. Eur. J. Med. Chem.195, 112267. 10.1016/j.ejmech.2020.112267

  • CrossRef
  • Google Scholar

• 71

  De WitT.BaekelandtV.LobbestaelE. (2018). Inhibition of LRRK2 or casein kinase 1 results in LRRK2 protein destabilization. Mol. Neurobiol.56, 5273–5286. 10.1007/s12035-018-1449-2

  • CrossRef
  • Google Scholar

• 72

  DesmondC. R.AtwalR. S.XiaJ.TruantR. (2012). Identification of a karyopherin β1/β2 proline-tyrosine nuclear localization signal in huntingtin protein. J. Biol. Chem.287, 39626–39633. 10.1074/jbc.M112.412379

  • CrossRef
  • Google Scholar

• 73

  DheenS. T.JunY.YanZ.TayS. S. W.Ang LingE. (2005). Retinoic acid inhibits expression of TNF-α and iNOS in activated rat microglia. Glia50, 21–31. 10.1002/glia.20153

  • CrossRef
  • Google Scholar

• 74

  DillonG. M.HendersonJ. L.BaoC.JoyceJ. A.CalhounM.AmaralB.et al (2020). Acute inhibition of the CNS-specific kinase TTBK1 significantly lowers tau phosphorylation at several disease relevant sites. PLOS ONE15 (4), e0228771. 10.1371/journal.pone.0228771

  • CrossRef
  • Google Scholar

• 75

  DomańskaK.ZielińskiR.KubińskiK.SajnagaE.MasłykM.BretnerM.et al (2005). Different properties of four molecular forms of protein kinase CK2 from Saccharomyces cerevisiae. Acta Biochim. Pol.52, 947–952. 10.18388/abp.2005_3413

  • CrossRef
  • Google Scholar

• 76

  DuanG.WaltherD. (2015). The roles of post-translational modifications in the context of protein interaction networks. PLoS Comput. Biol.11, e1004049. 10.1371/journal.pcbi.1004049

  • CrossRef
  • Google Scholar

• 77

  EbrahimiR.SepandM. R.SeyednejadS. A.OmidiA.AkbarianiM.GholamiM.et al (2019). Ellagic acid reduces methotrexate-induced apoptosis and mitochondrial dysfunction via up-regulating Nrf2 expression and inhibiting the IĸBα/NFĸB in rats. DARU27, 721–733. 10.1007/s40199-019-00309-9

  • CrossRef
  • Google Scholar

• 78

  El-AgnafO. M.JakesR.CurranM. D.WallaceA. (1998). Effects of the mutations Ala30 to Pro and Ala53 to Thr on the physical and morphological properties of α-synuclein protein implicated in Parkinson’s disease. FEBS Lett.440, 67–70. 10.1016/s0014-5793(98)01419-7

  • CrossRef
  • Google Scholar

• 79

  EllisC. E.SchwartzbergP. L.GriderT. L.FinkD. W.NussbaumR. L. (2001). alpha-synuclein is phosphorylated by members of the Src family of protein-tyrosine kinases. J. Biol. Chem.276, 3879–3884. 10.1074/jbc.M010316200

  • CrossRef
  • Google Scholar

• 80

  EvertB. O.AraujoJ.Vieira-SaeckerA. M.de VosR. A.HarendzaS.KlockgetherT.et al (2006). Ataxin-3 represses transcription via chromatin binding, interaction with histone deacetylase 3, and histone deacetylation. J. Neurosci.26, 11474–11486. 10.1523/JNEUROSCI.2053-06.2006

  • CrossRef
  • Google Scholar

• 81

  EvinG.SmithM. J.TziotisA.McLeanC.CanterfordL.SharplesR. A.et al (2002). Alternative transcripts of presenilin-1 associated with frontotemporal dementia. Neuroreport13, 917–921. 10.1097/00001756-200205070-00036

  • CrossRef
  • Google Scholar

• 82

  FarkhondehT.FolgadoS. L.Pourbagher-ShahriA. M.AshrafizadehM.SamarghandianS. (2020). The therapeutic effect of resveratrol: Focusing on the Nrf2 signaling pathway. Biomed. Pharmacother.127, 110234. 10.1016/j.biopha.2020.110234

  • CrossRef
  • Google Scholar

• 83

  FlajoletM.HeG.HeimanM.LinA.NairnA. C.GreengardP. (2007). Regulation of Alzheimer’s disease amyloid-beta formation by casein kinase I. Proc. Natl. Acad. Sci. U. S. A.104, 4159–4164. 10.1073/pnas.0611236104

  • CrossRef
  • Google Scholar

• 84

  FlotowH.RoachP. J. (1991). Role of acidic residues as substrate determinants for casein kinase I.J. Biol. Chem.266, 3724–3727. 10.1016/S0021-9258(19)67854-3

  • CrossRef
  • Google Scholar

• 85

  FranchinC.CesaroL.SalviM.MillioniR.IoriE.CifaniP.et al (2015). Quantitative analysis of a phosphoproteome readily altered by the protein kinase CK2 inhibitor quinalizarin in HEK-293T cells. Biochim. Biophys. Acta1854, 609–623. 10.1016/j.bbapap.2014.09.017

  • CrossRef
  • Google Scholar

• 86

  FujiwaraH.HasegawaM.DohmaeN.KawashimaA.MasliahE.GoldbergM. S.et al (2002). Alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat. Cell Biol.4, 160–164. 10.1038/ncb748

  • CrossRef
  • Google Scholar

• 87

  FukudaT.IshibashiF.IwaoM. (2020). Lamellarin alkaloids: Isolation, synthesis, and biological activity. Alkaloids. Chem. Biol.83, 1–112. 10.1016/bs.alkal.2019.10.001

  • CrossRef
  • Google Scholar

• 88

  FulcherL. J.SapkotaG. P. (2020). Functions and regulation of the serine/threonine protein kinase CK1 family: Moving beyond promiscuity. Biochem. J.477, 4603–4621. 10.1042/BCJ20200506

  • CrossRef
  • Google Scholar

• 89

  GaiW. P.PowerJ. H.BlumbergsP. C.BlessingW. W. (1998). Multiple-system atrophy: A new a-synuclein disease?Lancet352, 547–548. 10.1016/s0140-6736(05)79256-4

  • CrossRef
  • Google Scholar

• 90

  García-ReyesB.WittL.JansenB.KarasuE.GehringT.LebanJ.et al (2018). Discovery of inhibitor of Wnt production 2 (IWP-2) and related compounds as selective ATP-competitive inhibitors of casein kinase 1 (CK1) δ/ε. J. Med. Chem.61, 4087–4102. 10.1021/acs.jmedchem.8b00095

  • CrossRef
  • Google Scholar

• 91

  GeuensT.BouhyD.TimmermanV. (2016). The hnRNP family: Insights into their role in health and disease. Hum. Genet.135, 851–867. 10.1007/s00439-016-1683-5

  • CrossRef
  • Google Scholar

• 92

  GhoshalN.SmileyJ. F.DeMaggioA. J.HoekstraM. F.CochranE. J.BinderL. I.et al (1999). A new molecular link between the fibrillar and granulovacuolar lesions of Alzheimer’s disease. Am. J. Pathol.155, 1163–1172. 10.1016/s0002-9440(10)65219-4

  • CrossRef
  • Google Scholar

• 93

  GlennerG. G.WongC. W. (1984). Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun.120, 885–890. 10.1016/s0006-291x(84)80190-4

  • CrossRef
  • Google Scholar

• 94

  GolubA. G.BdzholaV. G.BriukhovetskaN. V.BalandaA. O.KukharenkoO. P.KoteyI. M.et al (2011). Synthesis and biological evaluation of substituted (thieno[2, 3-d]pyrimidin-4-ylthio)carboxylic acids as inhibitors of human protein kinase CK2. Eur. J. Med. Chem.46, 870–876. 10.1016/j.ejmech.2010.12.025

  • CrossRef
  • Google Scholar

• 95

  GomesB. A. Q.SilvaJ. P. B.RomeiroC. F. R.dos SantosS. M.RodriguesC. A.GonçalvesP. R.et al (2018). Neuroprotective mechanisms of resveratrol in Alzheimer’s disease: Role of SIRT1. Oxid. Med. Cell. Longev.2018, 8152373. 10.1155/2018/8152373

  • CrossRef
  • Google Scholar

• 96

  GongC.-X.IqbalK. (2008). Hyperphosphorylation of microtubule-associated protein tau: A promising therapeutic target for alzheimer disease. Curr. Med. Chem.15, 2321–2328. 10.2174/092986708785909111

  • CrossRef
  • Google Scholar

• 97

  GongC.-X.SinghT. J.Grundke-IqbalI.IqbalK. (1993). Phosphoprotein phosphatase activities in Alzheimer disease brain. J. Neurochem.61, 921–927. 10.1111/j.1471-4159.1993.tb03603.x

  • CrossRef
  • Google Scholar

• 98

  GreenwoodJ. A.ScottC. W.SpreenR. C.CaputoC. B.JohnsonG. V. (1994). Casein kinase II preferentially phosphorylates human tau isoforms containing an amino-terminal insert. Identification of threonine 39 as the primary phosphate acceptor. J. Biol. Chem.269, 4373–4380. 10.1016/S0021-9258(17)41790-x

  • CrossRef
  • Google Scholar

• 99

  Grundke-IqbalI.IqbalK.TungY. C.QuinlanM.WisniewskiH. M.BinderL. I. (1986). Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. U. S. A.83, 4913–4917. 10.1073/pnas.83.13.4913

  • CrossRef
  • Google Scholar

• 100

  GuoD.-J.LiF.YuP. H.-F.ChanS.-W. (2013). Neuroprotective effects of luteolin against apoptosis induced by 6-hydroxydopamine on rat pheochromocytoma PC12 cells. Pharm. Biol.51, 190–196. 10.3109/13880209.2012.716852

  • CrossRef
  • Google Scholar

• 101

  HackamA. S.SingarajaR.WellingtonC. L.MetzlerM.McCutcheonK.ZhangT.et al (1998). The influence of huntingtin protein size on nuclear localization and cellular toxicity. J. Cell Biol.141, 1097–1105. 10.1083/jcb.141.5.1097

  • CrossRef
  • Google Scholar

• 102

  HaidarS.AicheleD.BirusR.HielscherJ.LaitinenT.PosoA.et al (2019). In vitro and in silico evaluation of bikaverin as a potent inhibitor of human protein kinase CK2. Molecules24, 1380. 10.3390/molecules24071380

  • CrossRef
  • Google Scholar

• 103

  HalekotteJ.WittL.IanesC.KrügerM.BührmannM.RauhD.et al (2017). Optimized 4, 5-diarylimidazoles as potent/selective inhibitors of protein kinase CK1δ and their structural relation to p38α MAPK. Molecules22, 522. 10.3390/molecules22040522

  • CrossRef
  • Google Scholar

• 104

  HalkinaT.HendersonJ. L.LinE. Y.HimmelbauerM. K.JonesJ. H.NevalainenM.et al (2021). Discovery of potent and brain-penetrant tau tubulin kinase 1 (TTBK1) inhibitors that lower tau phosphorylation in vivo. J. Med. Chem.64, 6358–6380. 10.1021/acs.jmedchem.1c00382

  • CrossRef
  • Google Scholar

• 105

  HampeC.Ardila-OsorioH.FournierM.BriceA.CortiO. (2006). Biochemical analysis of Parkinson’s disease-causing variants of parkin, an E3 ubiquitin-protein ligase with monoubiquitylation capacity. Hum. Mol. Genet.15, 2059–2075. 10.1093/hmg/ddl131

  • CrossRef
  • Google Scholar

• 106

  HangerD. P.AndertonB. H.NobleW. (2009). Tau phosphorylation: The therapeutic challenge for neurodegenerative disease. Trends Mol. Med.15, 112–119. 10.1016/j.molmed.2009.01.003

  • CrossRef
  • Google Scholar

• 107

  HangerD. P.ByersH. L.WrayS.LeungK.-Y.SaxtonM. J.SeereeramA.et al (2007). Novel phosphorylation sites in tau from alzheimer brain support a role for casein kinase 1 in disease pathogenesis. J. Biol. Chem.282, 23645–23654. 10.1074/jbcM703269200

  • CrossRef
  • Google Scholar

• 108

  HanksS. K.HunterT. (1995). The eukaryotic protein kinase superfamily: Kinase (catalytic) domain structure and classification ¹. FASEB J.9, 576–596. 10.1096/fasebj.9.8.7768349

  • CrossRef
  • Google Scholar

• 109

  HardyJ. A.HigginsG. A. (1992). Alzheimer’s disease: The amyloid cascade hypothesis. Science1256, 184–185. 10.1126/science.1566067

  • CrossRef
  • Google Scholar

• 110

  HasegawaM.AraiT.NonakaT.KametaniF.YoshidaM.HashizumeY.et al (2008). Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann. Neurol.64, 60–70. 10.1002/Ana.21425

  • CrossRef
  • Google Scholar

• 111

  HathawayG. M.TraughJ. A. (1979). Cyclic nucleotide-independent protein kinases from rabbit reticulocytes. Purification of casein kinases. J. Biol. Chem.254, 762–768. 10.1016/S0021-9258(17)37871-7

  • CrossRef
  • Google Scholar

• 112

  Hinojosa-VenturaG.Puebla-PérezA. M.Gallegos-ArreolaM. P.Chávez-PargaM.-C.Romero-EstradaA.Delgado-SaucedoJ. I. (2019). Cytotoxic and antitumoral effects of bikaverin from Gibberella fujikuroi on L5178Y lymphoma murine model. J. Mex. Chem. Soc.63, 115–122. 10.29356/jmcs.v63i4.729

  • CrossRef
  • Google Scholar

• 113

  HouldenH.JohnsonJ.Gardner-ThorpeC.LashleyT.HernandezD.WorthP.et al (2007). Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11. Nat. Genet.39, 1434–1436. 10.1038/ng.2007.43

  • CrossRef
  • Google Scholar

• 114

  HuaZ.HuangX.BregmanH.ChakkaN.DiMauroE. F.DohertyE. M.et al (2012). 2-Phenylamino-6-cyano-1H-benzimidazole-based isoform selective casein kinase 1 gamma (CK1γ) inhibitors. Bioorg. Med. Chem. Lett.22, 5392–5395. 10.1016/j.bmcl.2012.07.046

  • CrossRef
  • Google Scholar

• 115

  HunterT. (1995). Protein kinases and phosphatases: The yin and yang of protein phosphorylation and signaling. Cell80, 225–236. 10.1016/0092-8674(95)90405-0

  • CrossRef
  • Google Scholar

• 116

  HunterT. (2012). Why nature chose phosphate to modify proteins. Philos. Trans. R. Soc. Lond. B Biol. Sci.367, 2513–2516. 10.1098/rstb.2012.0013

  • CrossRef
  • Google Scholar

• 117

  IkezuS.IkezuT. (2014). Tau-tubulin kinase. Front. Mol. Neurosci.7, 33. 10.3389/fnmol.2014.00033

  • CrossRef
  • Google Scholar

• 118

  IkezuS.Ingraham DixieK. L.KoroL.WatanabeT.KaibuchiK.IkezuT. (2020). Tau-tubulin kinase 1 and amyloid-β peptide induce phosphorylation of collapsin response mediator protein-2 and enhance neurite degeneration in Alzheimer disease mouse models. Acta Neuropathol. Commun.8, 12. 10.1186/s40478-020-0890-4

  • CrossRef
  • Google Scholar

• 119

  InukaiY.NonakaT.AraiT.YoshidaM.HashizumeY.BeachT. G.et al (2008). Abnormal phosphorylation of ser409/410 of TDP-43 in FTLD-U and ALS. FEBS Lett.582, 2899–2904. 10.1016/j.febslet.2008.07.027

  • CrossRef
  • Google Scholar

• 120

  IshiiA.NonakaT.TaniguchiS.SaitoT.AraiT.MannD.et al (2007). Casein kinase 2 is the major enzyme in brain that phosphorylates Ser129 of human alpha-synuclein: Implication for alpha-synucleinopathies. FEBS Lett.581, 4711–4717. 10.1016/j.febslet.2007.08.067

  • CrossRef
  • Google Scholar

• 121

  IwaoM.FukudaT.IshibashiF. (2011). Synthesis and biological activity of lamellarin alkaloids: An overview. HETEROCYCLES83, 491. 10.3987/rev-10-686

  • CrossRef
  • Google Scholar

• 122

  JacksonP. K. (2012). TTBK2 kinase: Linking primary cilia and cerebellar ataxias. Cell151, 697–699. 10.1016/j.cell.2012.10.027

  • CrossRef
  • Google Scholar

• 123

  JamesonL.FreyT.ZeebergB.DalldorfF.CaplowM. (1980). Inhibition of microtubule assembly by phosphorylation of microtubule-associated proteins. Biochemistry19, 2472–2479. 10.1021/bi00552a027

  • CrossRef
  • Google Scholar

• 124

  JanaS.SinghS. K. (2020). Identification of human tau-tubulin kinase 1inhibitors: An integrated e-pharmacophore based virtual screening and molecular dynamics simulation. J. Biomol. Struct. Dyn.38, 886–900. 10.1080/07391102.2019.1590242

  • CrossRef
  • Google Scholar

• 125

  JaneczkoM.OrzeszkoA.KazimierczukZ.SzyszkaR.BaierA. (2012). CK2α and CK2α′ subunits differ in their sensitivity to 4, 5, 6, 7-tetrabromo- and 4, 5, 6, 7-tetraiodo-1H-benzimidazole derivatives. Eur. J. Med. Chem.47, 345–350. 10.1016/j.ejmech.2011.11.002

  • CrossRef
  • Google Scholar

• 126

  JäråsM.MillerP. G.ChuL. P.PuramR. V.FinkE. C.SchneiderR. K.et al (2014). Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia. J. Exp. Med.211, 605–612. 10.1084/jem.20131033

  • CrossRef
  • Google Scholar

• 127

  JiangS.ZhangM.SunJ.YangX. (2018). Casein kinase 1α: Biological mechanisms and theranostic potential. Cell Commun. Signal.16, 23. 10.1186/s12964-018-0236-z

  • CrossRef
  • Google Scholar

• 128

  JinJ.PawsonT. (2012). Modular evolution of phosphorylation-based signalling systems. Philos. Trans. R. Soc. Lond. B Biol. Sci.367, 2540–2555. 10.1098/rstb.2012.0106

  • CrossRef
  • Google Scholar

• 129

  KametaniF.NonakaT.SuzukiT.AraiT.DohmaeN.AkiyamaH.et al (2009). Identification of casein kinase-1 phosphorylation sites on TDP-43. Biochem. Biophys. Res. Commun.382, 405–409. 10.1016/j.bbrc.2009.03.038

  • CrossRef
  • Google Scholar

• 130

  KangS. S.LeeJ. Y.ChoiY. K.KimG. S.HanB. H. (2004). Neuroprotective effects of flavones on hydrogen peroxide-induced apoptosis in SH-SY5Y neuroblostoma cells. Bioorg. Med. Chem. Lett.14, 2261–2264. 10.1016/j.bmcl.2004.02.003

  • CrossRef
  • Google Scholar

• 131

  KannanayakalT. J.TaoH.VandreD. D.KuretJ. (2006). Casein kinase-1 isoforms differentially associate with neurofibrillary and granulovacuolar degeneration lesions. Acta Neuropathol.111, 413–421. 10.1007/s00401-006-0049-9

  • CrossRef
  • Google Scholar

• 132

  KarveT. M.CheemaA. K. (2011). Small changes huge impact: The role of protein posttranslational modifications in cellular homeostasis and disease. J. Amino Acids2011, 207691. 10.4061/2011/207691

  • CrossRef
  • Google Scholar

• 133

  KieferS. E.ChangC. J.KimuraS. R.GaoM.XieD.ZhangY.et al (2014). The structure of human tau-tubulin kinase 1 both in the apo form and in complex with an inhibitor. Acta Crystallogr. F. Struct. Biol. Commun.70, 173–181. 10.1107/S2053230X14000144

  • CrossRef
  • Google Scholar

• 134

  KimE. N.LimJ. H.KimM. Y.BanT. H.JangI.YoonH. E.et al (2018). Resveratrol, an Nrf2 activator, ameliorates aging-related progressive renal injury. Aging (Albany NY)10, 83–99. 10.18632/aging.101361

  • CrossRef
  • Google Scholar

• 135

  KimH.ChoiK.KangH.LeeS.-Y.ChiS.-W.LeeM.-S.et al (2014). Identification of a novel function of CX-4945 as a splicing regulator. PLoS One9, e94978. 10.1371/journal.pone.0094978

  • CrossRef
  • Google Scholar

• 136

  KimJ. K.ParkS. U. (2021). Flavonoids for treatment of Alzheimer’s disease: An up todate review. EXCLI J.20, 495–502. 10.17179/excli2021-3492

  • CrossRef
  • Google Scholar

• 137

  KnippschildU.GochtA.WolffS.HuberN.LöhlerJ.StöterM. (2005). The casein kinase 1 family: Participation in multiple cellular processes in eukaryotes. Cell. Signal.17, 675–689. 10.1016/j.cellsig.2004.12.011

  • CrossRef
  • Google Scholar

• 138

  KomorowskaJ.WątrobaM.SzukiewiczD. (2020). Review of beneficial effects of resveratrol in neurodegenerative diseases such as Alzheimer’s disease. Adv. Med. Sci.65, 415–423. 10.1016/j.advms.2020.08.002

  • CrossRef
  • Google Scholar

• 139

  KostenJ.BinolfiA.StuiverM.VerziniS.TheilletF.-X.BekeiB.et al (2014). Efficient modification of alpha-synuclein serine 129 by protein kinase CK1 requires phosphorylation of tyrosine 125 as a priming event. ACS Chem. Neurosci.5, 1203–1208. 10.1021/cn5002254

  • CrossRef
  • Google Scholar

• 140

  KotanidouA.XagorariA.BagliE.KitsantaP.FotsisT.PapapetropoulosA.et al (2002). Luteolin reduces lipopolysaccharide-induced lethal toxicity and expression of proinflammatory molecules in mice. Am. J. Respir. Crit. Care Med.165, 818–823. 10.1164/ajrccm.165.6.2101049

  • CrossRef
  • Google Scholar

• 141

  KovacsG. G.BotondG.BudkaH. (2010). Protein coding of neurodegenerative dementias: The neuropathological basis of biomarker diagnostics. Acta Neuropathol.119, 389–408. 10.1007/s00401-010-0658-1

  • CrossRef
  • Google Scholar

• 142

  KumarA.SinghC. K.LaVoieH. A.DiPetteD. J.SinghU. S. (2011). Resveratrol Restores Nrf2 Level and Prevents Ethanol-Induced Toxic Effects in the Cerebellum of a Rodent Model of Fetal Alcohol Spectrum Disorders. Mol. Pharmacol.80, 446–457. 10.1124/mol.111.071126

  • CrossRef
  • Google Scholar

• 143

  KwonY. (2017). Luteolin as a potential preventive and therapeutic candidate for Alzheimer’s disease. Exp. Gerontol.95, 39–43. 10.1016/j.exger.2017.05.014

  • CrossRef
  • Google Scholar

• 144

  LaFerlaF. M.GreenK. N.OddoS. (2007). Intracellular amyloid-β in Alzheimer’s disease. Nat. Rev. Neurosci.8, 499–509. 10.1038/nrn2168

  • CrossRef
  • Google Scholar

• 145

  LasaM.MarinO.PinnaL. A. (1997). Rat liver Golgi apparatus contains a protein kinase similar to the casein kinase of lactating mam mary gland. Eur. J. Biochem.243, 719–725. 10.1111/j.1432-1033.1997.00719.x

  • CrossRef
  • Google Scholar

• 146

  Lastres-BeckerI.García-YagüeA. J.ScannevinR. H.CasarejosM. J.KüglerS.RábanoA.et al (2016). Repurposing the NRF2 activator dimethyl fumarate as therapy against synucleinopathy in Parkinson’s disease. Antioxid. Redox Signal.25, 61–77. 10.1089/ars.2015.6549

  • CrossRef
  • Google Scholar

• 147

  ŁawnickaH.Kowalewicz-KulbatM.SicińskaP.KazimierczukZ.GriebP.StępieńP. (2010). Anti-neoplastic effect of protein kinase CK2 inhibitor, 2-dimethylamino-4, 5, 6, 7-tetrabromobenzimidazole (DMAT), on growth and hormonal activity of human adrenocortical carcinoma cell line (H295R) in vitro. Cell Tissue Res.340, 371–379. 10.1007/s00441-010-0960-1

  • CrossRef
  • Google Scholar

• 148

  LeeJ. W.HirotaT.PetersE. C.GarciaM.GonzalezR.ChoC. Y.et al (2011). A small molecule modulates circadian rhythms through phosphorylation of the period protein. Angew. Chem. Int. Ed. Engl.50, 10608–10611. 10.1002/anie.201103915

  • CrossRef
  • Google Scholar

• 149

  LeeJ. Y.YunJ.-S.KimW.-K.ChunH.-S.JinH.ChoS.et al (2019). Structural basis for the selective inhibition of cdc2-like kinases by CX-4945. Biomed. Res. Int.2019, 6125068. 10.1155/2019/6125068

  • CrossRef
  • Google Scholar

• 150

  LeeV. M.GoedertM.TrojanowskiJ. Q. (2001). Neurodegenerative tauopathies. Annu. Rev. Neurosci.24, 1121–1159. 10.1146/annurev.neuro.24.1.1121

  • CrossRef
  • Google Scholar

• 151

  LiC.LiuX.LinX.ChenX. (2009). Structure-activity relationship of 7 flavonoids on recombinant human protein kinase CK2 holoenzyme. Zhong Nan Da Xue Xue Bao Yi Xue Ban.34, 20–26.

  • Google Scholar

• 152

  LiG.YinH.KurentJ. (2004). Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules. J. Biol. Chem.279, 15938–15945. 10.1074/jbc.M314116200

  • CrossRef
  • Google Scholar

• 153

  LiH.-Y.YehP.-A.ChiuH.-C.TangC.-Y.TuB. P.-h. (2011). Hyperphosphorylation as a defense mechanism to reduce TDP-43 aggregation. PLoS One6, e23075. 10.1371/journal.pone.0023075

  • CrossRef
  • Google Scholar

• 154

  LiK.McGeeL. R.FisherB.SudomA.LiuJ.RubensteinS. M.et al (2013). Inhibiting NF-κB-inducing kinase (NIK): Discovery, structure-based design, synthesis, structure–activity relationship, and co-crystal structures. Bioorg. Med. Chem. Lett.23, 1238–1244. 10.1016/j.bmcl.2013.01.012

  • CrossRef
  • Google Scholar

• 155

  LiM.MakkinjeA.DamuniZ. (1996). Molecular identification of I1PP2A, a novel potent heat-stable inhibitor protein of protein phosphatase 2A. Biochemistry35, 6998–7002. 10.1021/bi960581y

  • CrossRef
  • Google Scholar

• 156

  LiachkoN. F.McMillanP. J.StrovasT. J.LoomisE.GreenupL.MurrellJ. R.et al (2014). The tau tubulin kinases TTBK1/2 promote accumulation of pathological TDP-43. PLoS Genet.10, e1004803. 10.1371/journal.pgen.1004803

  • CrossRef
  • Google Scholar

• 157

  LiaoJ.-C.YangT. T.WengR. R.KuoC.-T.ChangC.-W. (2015). TTBK2: A tau protein kinase beyond tau phosphorylation. Biomed. Res. Int.2015, 575170. 10.1155/2015/575170

  • CrossRef
  • Google Scholar

• 158

  LindwallG.ColeR. D. (1984). Phosphorylation affects the ability of tau protein to promote microtubule assembly. J. Biol. Chem.259, 5301–5305. 10.1016/S0021-9258(17)42989-9

  • CrossRef
  • Google Scholar

• 159

  LippaC. F.FujiwaraH.MannD. M.GiassonB.BabaM.SchmidtM. L.et al (1998). Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes. Am. J. Pathol.153, 1365–1370. 10.1016/s0002-9440(10)65722-7

  • CrossRef
  • Google Scholar

• 160

  LitchfieldD. W. (2003). Protein kinase CK2: Structure, regulation and role in cellular decisions of life and death. Biochem. J.369, 1–15. 10.1042/bj20021469

  • CrossRef
  • Google Scholar

• 161

  LiuG.LiH.ZhangW.YuJ.ZhangX.WuR.et al (2021). Csnk1a1 inhibition modulates the inflammatory secretome and enhances response to radiotherapy in glioma. J. Cell. Mol. Med.25, 7395–7406. 10.1111/jcmm.16767

  • CrossRef
  • Google Scholar

• 162

  LiuJ.YiL.XiangZ.ZhongJ.ZhangH.SunT. (2015). Resveratrol attenuates spinal cord injury-induced inflammatory damage in rat lungs. Int. J. Clin. Exp. Pathol.8, 1237–1246.

  • Google Scholar

• 163

  LiuQ.-S.DengR.LiS.LiX.LiK.KebaituliG.et al (2017). Ellagic acid protects against neuron damage in ischemic stroke through regulating the ratio of Bcl-2/Bax expression. Appl. Physiol. Nutr. Metab.42, 855–860. 10.1139/apnm-2016-0651

  • CrossRef
  • Google Scholar

• 164

  LolliG.CozzaG.MazzoranaM.TibaldiE.CesaroL.Donella-DeanaA.et al (2012). Inhibition of protein kinase CK2 by flavonoids and tyrphostins. A structural insight. Biochemistry51, 6097–6107. 10.1021/bi300531c

  • CrossRef
  • Google Scholar

• 165

  Lopez-LazaroM. (2009). Distribution and biological activities of the flavonoid luteolin. Mini Rev. Med. Chem.9, 31–59. 10.2174/138955709787001712

  • CrossRef
  • Google Scholar

• 166

  LundH.CowburnR. F.GustafssonE.StrömbergK.SvenssonA.DahllundL.et al (2013). Tau-tubulin kinase 1 expression, phosphorylation and Co-localization with phospho-ser422 tau in the Alzheimer’s disease brain. Brain Pathol.23, 378–389. 10.1111/bpa.12001

  • CrossRef
  • Google Scholar

• 167

  LunkesA.LindenbergK. S.Ben-HaїemL.WeberC.DevysD.LandwehrmeyerG. B.et al (2002). Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions. Mol. Cell10, 259–269. 10.1016/s1097-2765(02)00602-0

  • CrossRef
  • Google Scholar

• 168

  MackenzieI. R.RademakersR.NeumannM. (2010). TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet. Neurol.9, 995–1007. 10.1016/S1474-4422(10)70195-2

  • CrossRef
  • Google Scholar

• 169

  MaherP.DarguschR.BodaiL.GerardP. E.PurcellJ. M.MarshJ. L. (2010). ERK activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington’s disease. Hum. Mol. Genet.20, 261–270. 10.1093/hmg/ddq460

  • CrossRef
  • Google Scholar

• 170

  MarconG.Di FedeG.GiacconeG.RossiG.GiovagnoliA. R.MaccagnanoE.et al (2009). A novel Italian presenilin 2 gene mutation with prevalent behavioral phenotype. J. Alzheimers Dis.16, 509–511. 10.3233/JAD-2009-0986

  • CrossRef
  • Google Scholar

• 171

  MarinO.MeggioF.SarnoS.AndrettaM.PinnaL. A. (1994). Phosphorylation of synthetic fragments of inhibitor-2 of protein phosphatase-1 by casein kinase-1 and -2. Evidence that phosphorylated residues are not strictly required for efficient targeting by casein kinase-1. Eur. J. Biochem.223, 647–653. 10.1111/j.1432-1033.1994.tb19037.x

  • CrossRef
  • Google Scholar

• 172

  MaroteauxL.CampanelliJ. T.SchellerR. H. (1988). Synuclein: A neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J. Neurosci.8, 2804–2815. 10.1523/JNEUROSCI.08-08-02804.1988

  • CrossRef
  • Google Scholar

• 173

  Martínez-GonzálezL.Rodríguez-CuetoC.CabezudoD.BartoloméF.Andrés-BenitoP.FerrerI.et al (2020). Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment. Sci. Rep.10, 4449. 10.1038/s41598-020-61265-y

  • CrossRef
  • Google Scholar

• 174

  MashhoonN.De MaggioA. J.TereshkoV.BergmeierS. C.EgliM.HoekstraM. F.et al (2000). Crystal structure of a conformation-selective casein kinase-1 inhibitor. J. Biol. Chem.275, 20052–20060. 10.1074/jbcM001713200

  • CrossRef
  • Google Scholar

• 175

  MbefoM. K.FaresM.-B.PaleologouK.OueslatiA.YinG.TenreiroS.et al (2015). Parkinson disease mutant E46K enhances α-synuclein phosphorylation in mammalian cell lines, in yeast, and in vivo. J. Biol. Chem.290, 9412–9427. 10.1074/jbc.m114.610774

  • CrossRef
  • Google Scholar

• 176

  MeggioF.MarinO.PinnaL. A. (1994). Substrate specificity of protein kinase CK2. Cell. Mol. Biol. Res.40, 401–409.

  • Google Scholar

• 177

  MeggioF.PerichJ. W.MarinO.PinnaL. A. (1992). The comparative efficiencies of the Ser(P)-Thr(P)- and Tyr(P)-residues as specificity determinants for casein kinase-1. Biochem. Biophys. Res. Commun.182, 1460–1465. 10.1016/0006-291x(92)91898-z

  • CrossRef
  • Google Scholar

• 178

  MeggioF.PerichJ. W.ReynoldsE. C.PinnaL. A. (1991). A synthetic β-casein phosphopeptide and analogues as model substrates for casein kinase-1, a ubiquitous, phosphate directed protein kinase. FEBS Lett.283, 303–306. 10.1016/0014-5793(91)80614-9

  • CrossRef
  • Google Scholar

• 179

  MeggioF.PinnaL. A. (2003). One-thousand-and-one substrates of protein kinase CK2?FASEB J.17, 349–368. 10.1096/fj.02-0473rev

  • CrossRef
  • Google Scholar

• 180

  MeijerL.BorgneA.MulnerO.ChongJ. P.BlowJ. J.InagakiN.et al (1997). Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur. J. Biochem.243, 527–536. 10.1111/j.1432-1033.1997.t01-2-00527.x

  • CrossRef
  • Google Scholar

• 181

  MeijerL.ThunnissenA.-M.WhiteA.GarnierM.NikolicM.TsaiL.-H.et al (2000). Inhibition of cyclin-dependent kinases, GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent.Chem. Biol.7, 51–63. 10.1016/s1074-5521(00)00063-6

  • CrossRef
  • Google Scholar

• 182

  MengQ.-J.MaywoodE. S.BechtoldD. A.LuW.-Q.LiJ.GibbsJ. E.et al (2010). Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes. Proc. Natl. Acad. Sci. U. S. A.107, 15240–15245. 10.1073/pnas.1005101107

  • CrossRef
  • Google Scholar

• 183

  MenkeR. A.JbabdiS.MillerK. L.MatthewsP. M.ZareiM. (2010). Connectivity-based segmentation of the substantia nigra in human and its implications in Parkinson's disease. Neuroimage52, 1175–1180. 10.1016/j.neuroimage.2010.05.086

  • CrossRef
  • Google Scholar

• 184

  MishraS.KinoshitaCh.AxtmanA. D.YoungJ. E. (2022). Evaluation of a selective chemical probe validates that CK2 mediates neuroinflammation in a human induced pluripotent stem cell-derived mircroglial model. Front. Mol. Neurosci.15, 824956. 10.3389/fnmol.2022.824956

  • CrossRef
  • Google Scholar

• 185

  Morales-GarciaJ. A.SaladoI. G.Sanz-San CristobalM.GilC.Pérez-CastilloA.MartínezA.et al (2017). Biological and pharmacological characterization of benzothiazole-based CK-1δ inhibitors in models of Parkinson’s disease. ACS Omega2, 5215–5220. 10.1021/acsomega.7b00869

  • CrossRef
  • Google Scholar

• 186

  MorookaS.HoshinaM.KiiI.OkabeT.KojimaH.InoueN.et al (2015). Identification of a dual inhibitor of SRPK1 and CK2 that attenuates pathological angiogenesis of macular degeneration in mice. Mol. Pharmacol.88, 316–325. 10.1124/mol.114.097345

  • CrossRef
  • Google Scholar

• 187

  MuellerT.BreuerP.SchmittI.WalterJ.EvertB. O.WüllnerU. (2009). CK2-dependent phosphorylation determines cellular localization and stability of ataxin-3. Hum. Mol. Genet.18, 3334–3343. 10.1093/hmg/ddp274

  • CrossRef
  • Google Scholar

• 188

  MurphyM. P.LeVineH. (2010). Alzheimer’s disease and the amyloid-β peptide. J. Alzheimer’s Dis.19, 311–323. 10.3233/jad-2010-1221

  • CrossRef
  • Google Scholar

• 189

  NakagawaT.OhtaK. (2019). Quercetin regulates the integrated stress response to improve memory. Int. J. Mol. Sci.20, 2761. 10.3390/ijms20112761

  • CrossRef
  • Google Scholar

• 190

  NakamuraT.YamashitaH.TakahashiT.NakamuraS. (2001). Activated Fyn phosphorylates alpha-synuclein at tyrosine residue 125. Biochem. Biophys. Res. Commun.280, 1085–1092. 10.1006/bbrc.2000.4253

  • CrossRef
  • Google Scholar

• 191

  NakielnyS.DreyfussG. (1997). Nuclear export of proteins and RNAs. Curr. Opin. Cell Biol.9, 420–429. 10.1016/s0955-0674(97)80016-6

  • CrossRef
  • Google Scholar

• 192

  NarhiL.WoodS. J.SteavensonS.JiangY.WuG. M.AnafiD.et al (1999). Both familial Parkinson’s disease mutations accelerate alpha-synuclein aggregation. J. Biol. Chem.274, 9843–9846. 10.1074/jbc.274.14.9843

  • CrossRef
  • Google Scholar

• 193

  NegroA.BrunatiA. M.Donella-DeanaA.MassiminoM. L.PinnaL. A. (2002). Multiple phosphorylation of alpha-synuclein by protein tyrosine kinase Syk prevents eosin-induced aggregation. FASEB J.16, 210–212. 10.1096/fj.01-0517fje

  • CrossRef
  • Google Scholar

• 194

  NeumannM.BentmannE.DormannD.JawaidA.DeJesus-HernandezM.AnsorgeO.et al (2011). FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations. Brain134, 2595–2609. 10.1093/brain/awr201

  • CrossRef
  • Google Scholar

• 195

  NeumannM.SampathuD. M.KwongL. K.TruaxA. C.MicsenyiM. C.ChouT. T.et al (2006). Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science314, 130–133. 10.1126/science.1134108

  • CrossRef
  • Google Scholar

• 196

  NirmaladeviD.VenkataramanaM.ChandranayakaS.RameshaA.JameelN. M.SrinivasC. (2014). Neuroprotective effects of bikaverin on H₂O₂-induced oxidative stress mediated neuronal damage in SH-SY5Y cell line. Cell. Mol. Neurobiol.34, 973–985. 10.1007/s10571-014-0073-6

  • CrossRef
  • Google Scholar

• 197

  NishiH.ShaytanA.PanchenkoA. R. (2014). Physicochemical mechanisms of protein regulation by phosphorylation. Front. Genet.5, 270. 10.3389/fgene.2014.00270

  • CrossRef
  • Google Scholar

• 198

  NonakaT.SuzukiG.TanakaY.KametaniF.HiraiS.OkadoH.et al (2016). Phosphorylation of TAR DNA-binding protein of 43 kDa (TDP-43) by truncated casein kinase 1 delta triggers mislocalization and accumulation of TDP-43. J. Biol. Chem.291, 5473–5483. 10.1074/jbc.M115.695379

  • CrossRef
  • Google Scholar

• 199

  NozalV.MartinezA. (2019). Tau Tubulin Kinase 1 (TTBK1), a new player in the fight against neurodegenerative diseases. Eur. J. Med. Chem.161, 39–47. 10.1016/j.ejmech.2018.10.030

  • CrossRef
  • Google Scholar

• 200

  NozalV.Martínez-GonzálezL.Gomez-AlmeriaM.Gonzalo-ConsuegraC.SantanaP.ChaikuadA.et al (2022). TDP-43 modulation by tau-tubulin kinase 1 inhibitors: A new avenue for future amyotrophic lateral sclerosis therapy. J. Med. Chem.65, 1585–1607. 10.1021/acs.jmedchem.1c01942

  • CrossRef
  • Google Scholar

• 201

  O’BrienR. J.WongP. C. (2011). Amyloid precursor protein processing and Alzheimer’s disease. Annu. Rev. Neurosci.34, 185–204. 10.1146/annurev-neuro-061010-113613

  • CrossRef
  • Google Scholar

• 202

  OkochiM.WalterJ.KoyamaA.NakajoS.BabaM.IwatsuboT.et al (2000). Constitutive phosphorylation of the Parkinson’s disease associated alpha-synuclein. J. Biol. Chem.275, 390–397. 10.1074/jbc.275.1.390

  • CrossRef
  • Google Scholar

• 203

  OliveiraJ.CostaM.de AlmeidaM. S. C.da Cruz e SilvaO. A. B.HenriquesA. G. (2017). Protein phosphorylation is a key mechanism in Alzheimer’s disease. J. Alzheimer’s Dis.58, 953–978. 10.3233/jad-170176

  • CrossRef
  • Google Scholar

• 204

  OshimaT.NiwaY.KuwataK.SrivastavaA.HyodaT.TsuchiyaY.et al (2019). Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth. Sci. Adv.5, eaau9060. 10.1126/sciadv.aau9060

  • CrossRef
  • Google Scholar

• 205

  OuS. H.WuF.HarrichD.Garcia-MartinezL. F.GaynorR. B. (1995). Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J. Virol.69, 3584–3596. 10.1128/JVI.69.6.3584-3596.1995

  • CrossRef
  • Google Scholar

• 206

  OueslatiA. (2016). Implication of alpha-synuclein phosphorylation at S129 in synucleinopathies: What have we learned in the last decade?J. Park. Dis.6, 39–51. 10.3233/JPD-160779

  • CrossRef
  • Google Scholar

• 207

  PaganoM. A.BainJ.KazimierczukZ.SarnoS.RuzzeneM.Di MairaG.et al (2008). The selectivity of inhibitors of protein kinase CK2: An update. Biochem. J.415, 353–365. 10.1042/bj20080309

  • CrossRef
  • Google Scholar

• 208

  PaleologouK. E.SchmidA. W.RospigliosiC. C.KimH.-Y.LambertoG. R.FredenburgR. A.et al (2008). Phosphorylation at ser-129 but not the phosphomimics S129E/D inhibits the fibrillation of α-synuclein. J. Biol. Chem.283, 16895–16905. 10.1074/jbc.m800747200

  • CrossRef
  • Google Scholar

• 209

  PalomoV.NozalV.Rojas-PratsE.GilC.MartinezA. (2020). Protein kinase inhibitors for amyotrophic lateral sclerosis therapy. Br. J. Pharmacol.178, 1316–1335. 10.1111/bph.15221

  • CrossRef
  • Google Scholar

• 210

  PerezD. I.GilC.MartinezA. (2011). Protein kinases CK1 and CK2 as new targets for neurodegenerative diseases.Med. Res. Rev.31, 924–954. 10.1002/med.20207

  • CrossRef
  • Google Scholar

• 211

  PierreF.ChuaP. C.O’BrienS. E.Siddiqui-JainA.BourbonP.HaddachM.et al (2011). Pre-clinical characterization of CX-4945, a potent and selective small molecule inhibitor of CK2 for the treatment of cancer. Mol. Cell. Biochem.356, 37–43. 10.1007/s11010-011-0956-5

  • CrossRef
  • Google Scholar

• 212

  PinnaL. A. (2002). Protein kinase CK2: A challenge to canons. J. Cell Sci.115, 3873–3878. 10.1242/jcs.00074

  • CrossRef
  • Google Scholar

• 213

  PlissonF.PrasadP.XiaoX.PiggottA. M.HuangX.KhalilZ.et al (2014). Callyspongisines A–D: Bromopyrrole alkaloids from an Australian marine sponge, callyspongia sp. Org. Biomol. Chem.12, 1579–1584. 10.1039/c4ob00091a

  • CrossRef
  • Google Scholar

• 214

  PosaD.Martinez-GonzalezL.BartolomeF.NagarajS.PorrasG.MartinezA.et al (2019). Recapitulation of pathological TDP-43 features in immortalized lymphocytes from sporadic ALS patients. Mol. Neurobiol.56, 2424–2432. 10.1007/s12035-018-1249-8

  • CrossRef
  • Google Scholar

• 215

  PotjewydF. M.MarquezA. B.ChaikuadA.HowelS.DunnA. S.BeltranA. A.et al (2022). Modulation of tau tubulin kinases (TTBK1 and TTBK2) impacts ciliogenesis. bioRxiv2022, 06490937. 10.1101/2022.05.06.490937

  • CrossRef
  • Google Scholar

• 216

  PulgarV.MarinO.MeggioF.AllendeC. C.AllendeJ. E.PinnaL. A. (1999). Optimal sequences for non-phosphate-directed phosphorylation by protein kinase CK1 (casein kinase-1)--a re-evaluation.Eur. J. Biochem.260, 520–526. 10.1046/j.1432-1327.1999.00195.x

  • CrossRef
  • Google Scholar

• 217

  RauxG.GantierR.MartinC.PothinY.BriceA.FrebourgT.et al (2000). A novel presenilin 1 missense mutation (L153V) segregating with early-onset autosomal dominant Alzheimer’s disease. Hum. Mutat.16, 95. 10.1002/1098-1004(200007)16:1<95:AID-HUMU28>3.0.CO;2-H

  • CrossRef
  • Google Scholar

• 218

  RegalL.VanopdenboschL.TilkinP.Van den BoschL.ThijsV.SciotR.et al (2006). The G93C mutation in superoxide dismutase 1: Clinicopathologic phenotype and prognosis. Arch. Neurol.63, 262–267. 10.1001/archneur.63.2.262

  • CrossRef
  • Google Scholar

• 219

  ReinerA.AlbinR. L.AndersonK. D.D’AmatoC. J.PenneyJ. B.YoungA. B. (1988). Differential loss of striatal projection neurons in Huntington disease. Proc. Natl. Acad. Sci. U. S. A.85, 5733–5737. 10.1073/pnas.85.15.5733

  • CrossRef
  • Google Scholar

• 220

  RenaG.BainJ.ElliottM.CohenP. (2004). D4476, a cell-permeant inhibitor of CK1, suppresses the site-specific phosphorylation and nuclear exclusion of FOXO1a. EMBO Rep.5, 60–65. 10.1038/sj.embor.7400048

  • CrossRef
  • Google Scholar

• 221

  RentonA. E.ChiòA.TraynorB. J. (2013). State of play in amyotrophic lateral sclerosis genetics. Nat. Neurosci.17, 17–23. 10.1038/nn.3584

  • CrossRef
  • Google Scholar

• 222

  Rezai-ZadehK.ShytleR. D.BaiY.TianJ.HouH.MoriT.et al (2009). Flavonoid-mediated presenilin-1 phosphorylation reduces Alzheimer's disease beta-amyloid production. J. Cell. Mol. Med.13, 574–588. 10.1111/j.1582-4934.2008.00344.x

  • CrossRef
  • Google Scholar

• 223

  RichterJ.BischofJ.ZajaM.KohlhofH.OthersenO.VittD.et al (2014). Difluoro-dioxolo-benzoimidazol-benzamides as potent inhibitors of CK1δ and ε with nanomolar inhibitory activity on cancer cell proliferation. J. Med. Chem.57, 7933–7946. 10.1021/jm500600b

  • CrossRef
  • Google Scholar

• 224

  RíosJ.-L.GinerR.MarínM.RecioM. (2018). A pharmacological update of ellagic acid. Planta Med.84, 1068–1093. 10.1055/a-0633-9492

  • CrossRef
  • Google Scholar

• 225

  RobberechtW.PhilipsT. (2013). The changing scene of amyotrophic lateral sclerosis. Nat. Rev. Neurosci.14, 248–264. 10.1038/nrn3430

  • CrossRef
  • Google Scholar

• 226

  RosenbergerA. F. N.MorremaT. H. J.GerritsenW. H.van HaastertE. S.SnkhchyanH.HilhorstR.et al (2016). Increased occurrence of protein kinase CK2 in astrocytes in Alzheimer’s disease pathology. J. Neuroinflammation13, 4. 10.1186/s12974-015-0470-x

  • CrossRef
  • Google Scholar

• 227

  RosenblattA. (2007). Neuropsychiatry of Huntington’s disease. Dialogues Clin. Neurosci.9, 191–197. 10.31887/DCNS.2007.9.2/arosenblatt

  • CrossRef
  • Google Scholar

• 228

  RubinszteinD. C.LeggoJ.ColesR.AlmqvistE.BiancalanaV.CassimanJ. J.et al (1996). Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats. Am. J. Hum. Genet.59, 16–22.

  • Google Scholar

• 229

  Rubio de la TorreE.Luzon-ToroB.Forte-LagoI.Minguez-CastellanosA.FerrerI.HilfikerS. (2009). Combined kinase inhibition modulates Parkin inactivation. Hum. Mol. Genet.18, 809–823. 10.1093/hmg/ddn407

  • CrossRef
  • Google Scholar

• 230

  SaladoI. G.RedondoM.BelloM. L.PerezC.LiachkoN. F.KraemerB. C.et al (2014). Protein kinase CK-1 inhibitors as new potential drugs for amyotrophic lateral sclerosis.J. Med. Chem.57, 2755–2772. 10.1021/jm500065f

  • CrossRef
  • Google Scholar

• 231

  SalviM.SarnoS.CesaroL.NakamuraH.PinnaL. A. (2009). Extraordinary pleiotropy of protein kinase CK2 revealed by weblogo phosphoproteome analysis. Biochim. Biophys. Acta1793, 847–859. 10.1016/j.bbamcr.2009.01.013

  • CrossRef
  • Google Scholar

• 232

  SannerudR.EsselensC.EjsmontP.MatteraR.RochinL.TharkeshwarA. K.et al (2016). Restricted location of PSEN2/γ-secretase determines substrate specificity and generates an intracellular Aβ pool. Cell166, 193–208. 10.1016/j.cell.2016.05.020

  • CrossRef
  • Google Scholar

• 233

  SarnoS.ReddyH.MeggioF.RuzzeneM.DaviesS. P.Donella-DeanaA.et al (2001). Selectivity of 4, 5, 6, 7-tetrabromobenzotriazole, an ATP site-directed inhibitor of protein kinase CK2 (“casein kinase-2”). FEBS Lett.496, 44–48. 10.1016/s0014-5793(01)02404-8

  • CrossRef
  • Google Scholar

• 234

  SatoN.HoriO.YamaguchiA.LambertJ. C.Chartier-HarlinM. C.RobinsonP. A.et al (1999). A novel presenilin-2 splice variant in human Alzheimer’s disease brain tissue. J. Neurochem.72, 2498–2505. 10.1046/j.1471-4159.1999.0722498.x

  • CrossRef
  • Google Scholar

• 235

  SatoS.CernyR. L.BuescherJ. L.IkezuT. (2006). Tau-tubulin kinase 1 (TTBK1), a neuron-specific tau kinase candidate, is involved in tau phosphorylation and aggregation. J. Neurochem.98, 1573–1584. 10.1111/j.1471-4159.2006.04059.x

  • CrossRef
  • Google Scholar

• 236

  SatoS.XuJ.OkuyamaS.MartinezL. B.WalshS. M.JacobsenM. T.et al (2008). Spatial learning impairment, enhanced CDK5/p35 activity, and downregulation of NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1. J. Neurosci.28, 14511–14521. 10.1523/jneurosci.3417-08.2008

  • CrossRef
  • Google Scholar

• 237

  SchwabC.DeMaggioA. J.GhoshalN.BinderL. I.KuretJ.McGeerP. L. (2000). Casein kinase 1 delta is associated with pathological accumulation of tau in several neurodegenerative diseases. Neurobiol. Aging21, 503–510. 10.1016/s0197-4580(00)00110-x

  • CrossRef
  • Google Scholar

• 238

  SchwartzP. A.MurrayB. W. (2011). Protein kinase biochemistry and drug discovery. Bioorg. Chem.39, 192–210. 10.1016/j.bioorg.2011.07.004

  • CrossRef
  • Google Scholar

• 239

  SchwindL.NalbachL.ZimmerA. D.KostelnikK. B.MenegattiJ.GrässerF.et al (2017). Quinalizarin inhibits adipogenesis through down-regulation of transcription factors and microRNA modulation. Biochim. Biophys. Acta. Gen. Subj.1861, 3272–3281. 10.1016/j.bbagen.2017.09.018

  • CrossRef
  • Google Scholar

• 240

  SelvakumarK.BavithraS.SuganthiM.BensonC. S.ElumalaiP.ArunkumarR.et al (2012). Protective role of quercetin on PCBs-induced oxidative stress and apoptosis in hippocampus of adult rats. Neurochem. Res.37, 708–721. 10.1007/s11064-011-0661-5

  • CrossRef
  • Google Scholar

• 241

  ShaoG.ChenS.SunY.XuH.GeF. (2021). Chrysoeriol promotes functional neurological recovery in a rat model of cerebral ischemia. Phcog. Mag.17, 802–810. 10.4103/pm.pm_329_21

  • CrossRef
  • Google Scholar

• 242

  SharmaV.MishraM.GhoshS.TewariR.BasuA.SethP.et al (2007). Modulation of interleukin-1beta mediated inflammatory response in human astrocytes by flavonoids: Implications in neuroprotection. Brain Res. Bull.73, 55–63. 10.1016/j.brainresbull.2007.01.016

  • CrossRef
  • Google Scholar

• 243

  ShimuraH.HattoriN.KuboS.MizunoY.AsakawaS.MinoshimaS.et al (2000). Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat. Genet.25, 302–305. 10.1038/77060

  • CrossRef
  • Google Scholar

• 244

  Siddiqui-JainA.DryginD.StreinerN.ChuaP.PierreF.O'BrienS. E.et al (2010). CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy.Cancer Res.70, 10288–10298. 10.1158/0008-5472.CAN-10-1893

  • CrossRef
  • Google Scholar

• 245

  SmithM. J.SharplesR. A.EvinG.McLeanC. A.DeanB.PaveyG.et al (2004). Expression of truncated presenilin 2 splice variant in Alzheimer’s disease, bipolar disorder, and schizophrenia brain cortex. Brain Res. Mol. Brain Res.127, 128–135. 10.1016/j.molbrainres.2004.05.019

  • CrossRef
  • Google Scholar

• 246

  SpillantiniM. G.SchmidtM. L.LeeV. M.TrojanowskiJ. Q.JakesR.GoedertM. (1997). Alpha-synuclein in Lewy bodies. Nature388, 839–840. 10.1038/42166

  • CrossRef
  • Google Scholar

• 247

  SreedharanJ.BlairI. P.TripathiV. B.HuX.VanceC.RogeljB.et al (2008). TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science319, 1668–1672. 10.1126/science.1154584

  • CrossRef
  • Google Scholar

• 248

  SriramS. R.LiX.KoH. S.ChungK. K.WongE.LimK. L.et al (2005). Familial-associated mutations differentially disrupt the solubility, localization, binding and ubiquitination properties of parkin. Hum. Mol. Genet.14, 2571–2586. 10.1093/hmg/ddi292

  • CrossRef
  • Google Scholar

• 249

  SuC.-F.JiangL.ZhangX. W.IyaswamyA.LiM. (2021). Resveratrol in rodent models of Parkinson’s disease: A systematic review of experimental studies. Front. Pharmacol.12, 644219. 10.3389/fphar.2021.644219

  • CrossRef
  • Google Scholar

• 250

  SuZ.SongJ.WangZ.ZhouL.XiaY.YuS.et al (2018). Tumor promoter TPA activates Wnt/β-catenin signaling in a casein kinase 1-dependent manner. Proc. Natl. Acad. Sci. U. S. A.115, E7522–E7531. 10.1073/pnas.1802422115

  • CrossRef
  • Google Scholar

• 251

  SundaramS.NagarajS.MahoneyH.PortuguesA.LiW.MillsapsK.et al (2019). Inhibition of casein kinase 1δ/ε improves cognitive-affective behavior and reduces amyloid load in the APP-PS1 mouse model of Alzheimer’s disease. Sci. Rep.9, 13743. 10.1038/s41598-019-50197-x

  • CrossRef
  • Google Scholar

• 252

  SzyszkaR.GrankowskiN.FelczakK.ShugarD. (1995). Halogenated benzimidazoles and benzotriazoles as selective inhibitors of protein kinases CK-I and CK-ii from Saccharomyces cerevisiae and other sources. Biochem. Biophys. Res. Commun.208, 418–424. 10.1006/bbrc.1995.1354

  • CrossRef
  • Google Scholar

• 253

  TagliabracciV. S.WileyS. E.GuoX.KinchL. N.DurrantE.WenJ.et al (2015). A single kinase generates the majority of the secreted phosphoproteome. Cell161, 1619–1632. 10.1016/j.cell.2015.05.028

  • CrossRef
  • Google Scholar

• 254

  TakahashiM.TomizawaK.SatoK.OhtakeA.OmoriA. (1995). A novel tau-tubulin kinase from bovine brain. FEBS Lett.372, 59–64. 10.1016/0014-5793(95)00955-9

  • CrossRef
  • Google Scholar

• 255

  TakanoA.HoeH.-S.IsojimaY.NagaiK. (2004). Analysis of the expression, localization and activity of rat casein kinase 1epsilon-3.Neuroreport15, 1461–1464. 10.1097/01.wnr.0000133297.77278.81

  • CrossRef
  • Google Scholar

• 256

  TakashimaA.NoguchiK.SatoK.HoshomotoT.ImahoriK. (1993). Tau protein kinase I is essential for amyloid beta-protein-induced neurotoxicity. Proc. Natl. Acad. Sci. U. S. A.90, 7789–7793. 10.1073/pnas.90.16.7789

  • CrossRef
  • Google Scholar

• 257

  TanimukaiH.Grundke-IqbalI.IqbalK. (2005). Up-regulation of inhibitors of protein phosphatase-2A in Alzheimer’s disease. Am. J. Pathol.66, 1761–1771. 10.1016/S0002-9440(10)62486-8

  • CrossRef
  • Google Scholar

• 258

  TarrantM. K.ColeP. A. (2009). The chemical biology of protein phosphorylation. Annu. Rev. Biochem.78, 797–825. 10.1146/annurev.biochem.78.070907.103047

  • CrossRef
  • Google Scholar

• 259

  TaylorL. M.McMillanP. J.KraemerB. C.LiachkoN. F. (2019). Tau tubulin kinases in proteinopathy. FEBS J.286, 2434–2446. 10.1111/febs.14866

  • CrossRef
  • Google Scholar

• 260

  TaylorL. M.McMillanP. J.LiachkoN. F.StrovasT. J.GhettiB.BirdT. D.et al (2018). Pathological phosphorylation of tau and TDP-43 by TTBK1 and TTBK2 drives neurodegeneration. Mol. Neurodegener.13, 7. 10.1186/s13024-018-0237-9

  • CrossRef
  • Google Scholar

• 261

  TaylorS. S.KornevA. P. (2011). Protein kinases: Evolution of dynamic regulatory proteins. Trends biochem. Sci.36, 65–77. 10.1016/j.tibs.2010.09.006

  • CrossRef
  • Google Scholar

• 262

  TaylorS. S.Radzio-AndzelmE.HunterT. (1995). How do protein kinases discriminate between serine/threonine and tyrosine? Structural insights from the insulin receptor protein-tyrosine kinase. FASEB J.9, 1255–1266. 10.1096/fasebj.9.13.7557015

  • CrossRef
  • Google Scholar

• 263

  TianY.WangY.JablonskiA. M.HuY.SugamJ. A.KoglinM.et al (2021). Tau-tubulin kinase 1 phosphorylates TDP-43 at disease-relevant sites and exacerbates TDP-43 pathology. Neurobiol. Dis.161, 105548. 10.1016/j.nbd.2021.105548

  • CrossRef
  • Google Scholar

• 264

  TiwariS.AtluriV.KaushikA.YndarT. A.NairM. (2019). Alzheimer’s disease: Pathogenesis, diagnostics, and therapeutics. Int. J. Nanomedicine14, 5541–5554. 10.2147/IJN.S200490

  • CrossRef
  • Google Scholar

• 265

  TomizawaK.OmoriA.OhtakeA.SatoK.TakahashiM. (2001). Tau-tubulin kinase phosphorylates tau at Ser-208 and Ser-210, sites found in paired helical filament-tau. FEBS Lett.492, 221–227. 10.1016/s0014-5793(01)02256-6

  • CrossRef
  • Google Scholar

• 266

  TurnerR. S.ThomasR. G.CraftS.van DyckC. H.MintzerJ.ReynoldsB. A.et al (2015). A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology85, 1383–1391. 10.1212/wnl.0000000000002035

  • CrossRef
  • Google Scholar

• 267

  UedaK.FukushimaH.MasliahE.XiaY.IwaiA.YoshimotoM.et al (1993). Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc. Natl. Acad. Sci. U. S. A.90, 11282–11286. 10.1073/pnas.90.23.11282

  • CrossRef
  • Google Scholar

• 268

  UllahA.MunirS.BadshahS. L.KhanN.GhaniL.PoulsonB. G.et al (2020). Important flavonoids and their role as a therapeutic agent. Molecules25, 5243. 10.3390/molecules25225243

  • CrossRef
  • Google Scholar

• 269

  UverskyV. N. (2007). Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation. J. Neurochem.103, 17–37. 10.1111/j.1471-4159.2007.04764.x

  • CrossRef
  • Google Scholar

• 270

  VarelaL.Garcia-RenduelesM. E. R. (2022). Oncogenic pathways in neurodegenerative diseases. Int. J. Mol. Sci.23, 3223. 10.3390/ijms23063223

  • CrossRef
  • Google Scholar

• 271

  VargasM. R.PeharM.CassinaP.BeckmanJ. S.BarbeitoL. (2006). Increased glutathione biosynthesis by Nrf2 activation in astrocytes prevents p75NTR-dependent motor neuron apoptosis. J. Neurochem.97, 687–696. 10.1111/j.1471-4159.2006.03742.x

  • CrossRef
  • Google Scholar

• 272

  VassarR.BennettB. D.Babu-KahnS.KahnS.MendiazE. A.DenisP.et al (1999). Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science286, 735–741. 10.1126/science.286.5440.735

  • CrossRef
  • Google Scholar

• 273

  Vazquez-HigueraJ. L.Martinez-GarciaA.Sanchez-JuanP.Rodriguez-RodriguezE.MateoI.PozuetaA.et al (2011). Genetic variations in tau-tubulin kinase-1 are linked to Alzheimer’s disease in a Spanish case-control cohort. Neurobiol. Aging32, e5–9. 10.1016/j.neurobiolaging.2009.12.021

  • CrossRef
  • Google Scholar

• 274

  VenerandoA.RuzzeneM.PinnaL. A. (2014). Casein kinase: The triple meaning of a misnomer. Biochem. J.460, 141–156. 10.1042/bj20140178

  • CrossRef
  • Google Scholar

• 275

  VeraJ.EstanyolJ. M.CanelaN.LlorensF.AgellN.ItarteE.et al (2007). Proteomic analysis of SET-binding proteins. Proteomics7, 578–587. 10.1002/pmic.200600458

  • CrossRef
  • Google Scholar

• 276

  VersluysL.PereiraP. E.SchuermansN.De PaepeB.De BleeckerJ. L.BogaertE.et al (2022). Expanding the TDP-43 proteinopathy pathway from neurons to muscle: Physiological and pathophysiological functions. Front. Neurosci.16, 815765. 10.3389/fnins.2022.815765

  • CrossRef
  • Google Scholar

• 277

  WaddyC. T.MackinlayA. G. (1971). Protein kinase activity from lactating bovine mammary gland. Biochim. Biophys. Acta250, 491–500. 10.1016/0005-2744(71)90249-x

  • CrossRef
  • Google Scholar

• 278

  WagerT. T.ChandrasekaranR. Y.BradleyJ.RubitskiD.BerkeH.MenteS.et al (2014). Casein kinase 1δ/ε inhibitor PF-5006739 attenuates opioid drug-seeking behavior. ACS Chem. Neurosci.5, 1253–1265. 10.1021/cn500201x

  • CrossRef
  • Google Scholar

• 279

  WakabayashiK.MatsumotoK.TakayamaK.YoshimotoM.TakahashiH. (1997). NACP, a presynaptic protein, immunoreactivity in Lewy bodies in Parkinson’s disease. Neurosci. Lett.239, 45–48. 10.1016/s0304-3940(97)00891-4

  • CrossRef
  • Google Scholar

• 280

  WalterJ.CapellA.GrünbergJ.PesoldB.SchindzielorzA.PriorR.et al (1996). The Alzheimer's disease-associated presenilins are differentially phosphorylated proteins located predominantly within the endoplasmic reticulum. Mol. Med.2, 673–691. 10.1007/BF03401652

  • CrossRef
  • Google Scholar

• 281

  WalterJ.FluhrerR.HartungB.WillemM.KaetherC.CapellA.et al (2001). Phosphorylation regulates intracellular trafficking of β-secretase. J. Biol. Chem.276, 14634–14641. 10.1074/jbc.m011116200

  • CrossRef
  • Google Scholar

• 282

  WalterJ.SchindzielorzA.HartungB.HaassC. (2000). Phosphorylation of the beta-amyloid precursor protein at the cell surface by ectocasein kinases 1 and 2. J. Biol. Chem.275, 23523–23529. 10.1074/jbc.M002850200

  • CrossRef
  • Google Scholar

• 283

  WalterJ. (2000). The phosphorylation of presenilin proteins. Methods Mol. Med.32, 317–331. 10.1385/1-59259-195-7:317

  • CrossRef
  • Google Scholar

• 284

  WaltonK. M.FisherK.RubitskiD.MarconiM.MengQ.-J.SladekM.et al (2009). Selective inhibition of casein kinase 1 minimally alters circadian clock period. J. Pharmacol. Exp. Ther.330, 430–439. 10.1124/jpet.109.151415

  • CrossRef
  • Google Scholar

• 285

  WanY.HurW.ChoC. Y.LiuY.AdrianF. J.LozachO.et al (2004). Synthesis and target identification of hymenialdisine analogs. Chem. Biol.11, 247–259. 10.1016/j.chembiol.2004.01.015

  • CrossRef
  • Google Scholar

• 286

  WangB.LuZ.PolyaG. (1998). Inhibition of eukaryote serine/threonine-specific protein kinases by piceatannol. Planta Med.64, 195–199. 10.1055/s-2006-957407

  • CrossRef
  • Google Scholar

• 287

  WangQ.DongX.ZhangR.ZhaoCh. (2021). Flavonoids with potential anti-amyloidogenic effects as therapeutic drugs for treating alzheimer's disease. J. Alzheimers Dis.84, 505–533. 10.3233/JAD-210735

  • CrossRef
  • Google Scholar

• 288

  WangS.-H.LiangC.-H.LiangF.-P.DingH.-Y.LinS.-P.HuangG.-J.et al (2016). The inhibitory mechanisms study of 5, 6, 4′-trihydroxy-7, 3′-dimethoxyflavone against the LPS-induced macrophage inflammatory responses through the antioxidant ability. Molecules21, 136. 10.3390/molecules21020136

  • CrossRef
  • Google Scholar

• 289

  WaxmanE. A.GiassonB. I. (2008). Specificity and regulation of casein kinase/mediated phosphorylation of α-synuclein. J. Neuropathol. Exp. Neurol.67, 402–416. 10.1097/NEN.0b013e31816fc995

  • CrossRef
  • Google Scholar

• 290

  WeiY.ZhuG.ZhengC.LiJ.ShengS.LiD.et al (2020). Ellagic acid protects dopamine neurons from rotenone-induced neurotoxicity via activation of Nrf2 signalling. J. Cell. Mol. Med.24, 9446–9456. 10.1111/jcmm.15616

  • CrossRef
  • Google Scholar

• 291

  WeingartenM. D.LockwoodA. H.HwoS. Y.KirschnerM. W. (1975). A protein factor essential for microtubule assembly. Proc. Natl. Acad. Sci. U. S. A.72, 1858–1862. 10.1073/pnas.72.5.1858

  • CrossRef
  • Google Scholar

• 292

  WellsC. I.DrewryD. H.PickettJ. E.TjadenA.KrämerA.MüllerS.et al (2021). Development of a potent and selective chemical probe for the pleiotropic kinase CK2. Cell Chem. Biol.28, 546–558. e10. 10.1016/j.chembiol.2020.12.013

  • CrossRef
  • Google Scholar

• 293

  WirknerU.VossH.LichterP.AnsorgeW.PyerinW. (1994). The human gene (CSNK2A1) coding for the casein kinase II subunit alpha is located on chromosome 20 and contains tandemly arranged Alu repeats. Genomics19, 257–265. 10.1006/geno.1994.1056

  • CrossRef
  • Google Scholar

• 294

  XiaJ.LeeD. H.TaylorJ.VandelftM.TruantR. (2003). Huntingtin contains a highly conserved nuclear export signal. Hum. Mol. Genet.12, 1393–1403. 10.1093/hmg/ddg156

  • CrossRef
  • Google Scholar

• 295

  XuJ.SatoS.OkuyamaS.SwanR. J.JacobsenM. T.StrunkE.et al (2010). Tau-tubulin kinase 1 enhances prefibrillar tau aggregation and motor neuron degeneration in P301L FTDP-17 tau-mutant mice. FASEB J.24, 2904–2915. 10.1096/fj.09-150144

  • CrossRef
  • Google Scholar

• 296

  XuP.IanesC.GärtnerF.LiuC.BursterT.BakulevV.et al (2019). Structure, regulation, and (patho-)physiological functions of the stress-induced protein kinase CK1 delta (CSNK1D). Gene715, 144005. 10.1016/j.gene.2019.144005

  • CrossRef
  • Google Scholar

• 297

  XuY.DengY.QingH. (2015). The phosphorylation of α-synuclein: Development and implication for the mechanism and therapy of the Parkinson's disease.J. Neurochem.135, 4–18. 10.1111/jnc.13234

  • CrossRef
  • Google Scholar

• 298

  XueY.WanP. T.HillertzP.SchweikartF.ZhaoY.WisslerL.et al (2013). X-ray structural analysis of tau-tubulin kinase 1 and its interactions with small molecular inhibitors. ChemMedChem8, 1846–1854. 10.1002/cmdc.201300274

  • CrossRef
  • Google Scholar

• 299

  YadikarH.TorresI.AielloG.KurupM.YangZ.LinF.et al (2020). Screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization. PLOS ONE15, e0224952. 10.1371/journal.pone.0224952

  • CrossRef
  • Google Scholar

• 300

  YamamotoA.FriedleinA.ImaiY.TakahashiR.KahleP. J.HaassCh. (2005). Parkin phosphorylation and modulation of its E3 ubiquitin ligase activity. J. Biol. Chem.280, 3390–3399. 10.1074/jbc.M407724200

  • CrossRef
  • Google Scholar

• 301

  YangA. J. T.BagitA.MacPhersonR. E. K. (2021). Resveratrol, metabolic dysregulation, and Alzheimer’s disease: Considerations for neurogenerative disease. Int. J. Mol. Sci.22, 4628. 10.3390/ijms22094628

  • CrossRef
  • Google Scholar

• 302

  YangY.XuT.ZhangY.QinX. (2017). Molecular basis for the regulation of the circadian clock kinases CK1δ and CK1ε. Cell. Signal.31, 58–65. 10.1016/j.cellsig.2016.12.010

  • CrossRef
  • Google Scholar

• 303

  Yang-FengT. L.NaimanT.KopatzI.EliD.DafniN.CanaaniD. (1994). Assignment of the human casein kinase II alpha' subunit gene (CSNK2A1) to chromosome 16p13.2-p13.3.Genomics19, 173. 10.1006/geno.1994.1032

  • CrossRef
  • Google Scholar

• 304

  YasojimaK.SchwabC.McGeerE. G.McGeerP. L. (2000). Human neurons generate C-reactive protein and amyloid P: Upregulation in Alzheimer’s disease. Brain Res.887, 80–89. 10.1016/s0006-8993(00)02970-x

  • CrossRef
  • Google Scholar

• 305

  YdeC. W.FrogneT.LykkesfeldtA. E.FitchtnerI.IssingerO.-G.StenvangJ. (2007). Induction of cell death in antiestrogen resistant human breast cancer cells by the protein kinase CK2 inhibitor DMAT. Cancer Lett.256, 229–237. 10.1016/j.canlet.2007.06.010

  • CrossRef
  • Google Scholar

• 306

  YonetaniM.NonakaT.MasudaM.InukaiY.OikawaT.HisanagaS.et al (2009). Conversion of wildtype alpha-synuclein into mutant-type fibrils and its propagation in the presence of A30P mutant. J. Biol. Chem.284, 7940–7950. 10.1074/jbc.M807482200

  • CrossRef
  • Google Scholar

• 307

  YoshidaH.IharaY. (1993). Tau in paired helical filaments is functionally distinct from fetal tau: Assembly incompetence of paired helical filament-tau.J. Neurochem.61, 1183–1186. 10.1111/j.1471-4159.1993.tb03642.x

  • CrossRef
  • Google Scholar

• 308

  YuG.YanT.FengY.LiuX.XiaY.LuoH.et al (2013). Ser9 phosphorylation causes cytoplasmic detention of I₂^PP2A/SET in Alzheimer disease. Neurobiol. Aging34, 1748–1758. 10.1016/j.neurobiolaging.2012.12.025

  • CrossRef
  • Google Scholar

• 309

  YuN.-N.YuJ.-T.XiaoJ.-T.ZhangH.-W.LuR.-C.JiangH.et al (2011). Tau-tubulin kinase-1 gene variants are associated with Alzheimer’s disease in Han Chinese. Neurosci. Lett.491, 83–86. 10.1016/j.neulet.2011.01.011

  • CrossRef
  • Google Scholar

• 310

  YuP.WangL.TangF.ZengL.ZhouL.SongX.et al (2016). Resveratrol pretreatment decreases ischemic injury and improves neurological function via sonic hedgehog signaling after stroke in rats. Mol. Neurobiol.54, 212–226. 10.1007/s12035-015-9639-7

  • CrossRef
  • Google Scholar

• 311

  ZaplaticE.BuleM.ShahS. Z. A.UddinM. S.NiazK. (2019). Molecular mechanisms underlying protective role of quercetin in attenuating Alzheimer’s disease. Life Sci.224, 109–119. 10.1016/j.lfs.2019.03.055

  • CrossRef
  • Google Scholar

• 312

  ZhangH.KhalilZ.ConteM. M.PlissonF.CaponR. J. (2012). A search for kinase inhibitors and antibacterial agents: Bromopyrrolo-2-aminoimidazoles from a deep-water Great Australian Bight sponge Axinella sp. Tetrahedron Lett.53, 3784–3787. 10.1016/j.tetlet.2012.05.051

  • CrossRef
  • Google Scholar

• 313

  ZhangJ.GrossS. D.SchroederM. D.AndersonR. A. (1996). Casein kinase I α and αL: Alternative splicing-generated kinases exhibit different catalytic properties. Biochemistry35, 16319–16327. 10.1021/bi9614444

  • CrossRef
  • Google Scholar

• 314

  ZhangN.GordonS. L.FritschM. J.EsoofN.CampbellD. G.GourlayR.et al (2015). Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1. J. Neurosci.35, 2492–2507. 10.1523/JNEUROSCI.4248-14.2015

  • CrossRef
  • Google Scholar

• 315

  ZhangQ.XiaY.WangY.ShentuY.ZengK.MahamanY. A. R.et al (2018). CK2 phosphorylating I₂^PP2A/SET mediates tau pathology and cognitive impairment. Front. Mol. Neurosci.11, 146. 10.3389/fnmol.2018.00146

  • CrossRef
  • Google Scholar

• 316

  ZhangY.-J.XuY.-F.CookC.GendronT. F.RoettgesP.LinkC. D.et al (2009). Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proc. Natl. Acad. Sci. U. S. A.106, 7607–7612. 10.1073/pnas.0900688106

  • CrossRef
  • Google Scholar

• 317

  ZhaoH.MeiX.YangD.TuG. (2021). Resveratrol inhibits inflammation after spinal cord injury via SIRT-1/NF-κB signaling pathway. Neurosci. Lett.762, 136151. 10.1016/j.neulet.2021.136151

  • CrossRef
  • Google Scholar

• 318

  ZhaoZ.WangL.VolkA. G.BirchN. W.StoltzK. L.BartomE. T.et al (2018). Regulation of MLL/COMPASS stability through its proteolytic cleavage by taspase1 as a possible approach for clinical therapy of leukemia. Genes Dev.33, 61–74. 10.1101/gad.319830.118

  • CrossRef
  • Google Scholar

• 319

  ZhengH.KooE. H. (2006). The amyloid precursor protein: Beyond amyloid. Mol. Neurodegener.1, 5. 10.1186/1750-1326-1-5

  • CrossRef
  • Google Scholar

• 320

  ZhengJ. C.ChenS. (2022). Translational Neurodegeneration in the era of fast growing international brain research. Transl. Neurodegener.11, 1. 10.1186/s40035-021-00276-9

  • CrossRef
  • Google Scholar

• 321

  ZhouY.LiK.ZhangS.LiQ.LiZ.ZhouF.et al (2015). Quinalizarin, a specific CK2 inhibitor, reduces cell viability and suppresses migration and accelerates apoptosis in different human lung cancer cell lines. Indian J. Cancer52, e119–e124. 10.4103/0019-509X.172508

  • CrossRef
  • Google Scholar