Edited by: Andrei Surguchov, University of Kansas Medical Center, United States
Reviewed by: Irina G. Sourgoutcheva, University of Kansas Medical Center, United States; Nikolaus R. McFarland, University of Florida, United States
This article was submitted to Brain Disease Mechanisms, a section of the journal Frontiers in Molecular Neuroscience
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The term “atypical Parkinsonian syndromes” (APS) refers to chronic progressive neurodegenerative diseases with a common primary feature, parkinsonism with a poor or waning levodopa response and coexistence of additional “plus” features, hence, also often referred to as Parkinson-plus disorders. Progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration (CBD) can be distinguished among them. A shared pathogenetic feature of these disorders is abnormal protein accumulation in different brain regions. PSP and CBD are neuropathologically described as four-repeat tauopathies, conditions characterized by deposition of phosphorylated tau protein in neurons and glia, leading to toxicity and cell loss. Alpha-synuclein protein, the primary component of Lewy bodies, is also found in glial cytoplasmic inclusions characteristic of MSA (Dickson,
Studies assessing the use of dopaminergic drugs in the pharmacotherapy of atypical parkinsonism have shown ambiguous results. While some describe modest clinical improvement, the general therapeutic effect is rather insignificant (Kuran,
Since there is no disease-modifying treatment for progressive supranuclear palsy, therapy is currently focused on relieving clinical symptoms. Current approaches include botulinum toxin A (BtxA) injections used in focal dystonia (Müller et al.,
Potential novel therapies for atypical parkinsonian syndromes.
Progressive supranuclear palsy is an akinetic-rigid form of parkinsonism caused by intracerebral accumulation of the hyperphosphorylated microtubule-associated protein tau (MAPT). Abnormal aggregation of tau, a microtubule-binding protein, results in defective microtubule activity, a significant feature of this disease (Liu and Gong,
The prevalence of progressive supranuclear palsy is estimated by different studies to be approximately 6 per 100,000 (Schrag et al.,
Novel PSP therapeutic approaches are focused on slowing or halting disease progression, beyond only managing its physical, behavioral, and emotional symptoms. Recent studies have focused on treatment at the molecular level, not only examining genes responsible for tau protein synthesis and aggregation but also controlling molecules that participate in the degradation of misfolded-tau and prevention of oxidative stress (Boxer et al.,
Microglia are the most important immune modulator in the human nervous system (Maphis et al.,
Inflammation may also play a role in PSP, as it is commonly associated with tauopathies, despite limited evidence assessing the pathologic connection (Vagnozzi et al.,
A case-control study verifying the relationship between nonsteroidal anti-inflammatory drug (NSAID) intake and progressive supranuclear palsy symptoms showed no meaningful results. The authors emphasized that in order to obtain information on the correlation between NSAID use and change in the severity of PSP symptoms, a larger study should be conducted (Marras et al.,
Reduction of thiamine and thiamine-dependent enzyme activity resulted in tau phosphorylation, Aβ accumulation, and oxidative stress exacerbation, leading to increased interest in benfotiamine (BFT) as a potential PSP therapy (Tapias et al.,
Another drug believed to be important for future PSP treatment is tolfenamic acid (TA). Classified as an NSAID, TA is effective in pain reduction and lowering body temperature, and it exhibits characteristics of a possible anti-neoplastic molecule (PubChem,
Recently published data have highlighted the significance of mitochondrial dysfunction and oxidative stress in PSP. Studies on cells expressing mitochondrial genes found in patients with PSP revealed decreased activity of mitochondrial complexes I and III involved in ATP production and significant increases in antioxidant enzyme activity and markers of lipid oxidative damage, suggesting oxidative injury (Albers et al.,
Co-enzyme Q10 is a cofactor that stabilizes the mitochondrial respiratory chain and provides antioxidant properties (Saini,
Niacinamide is a form of vitamin B3, which, along with tryptophan, serves as a source of nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+), and their reduced forms (Makarov et al.,
α-Lipoic acid and L-acetyl carnitine, administered together, are thought to have a potential benefit for patients with PSP. This combination demonstrated neuroprotective properties in a rotenone-induced PD mouse model. Another study conducted with young and old rats supplemented with acetyl-L-carnitine (ALCAR) showed that ALCAR rescued age-related mitochondrial dysfunction, maintained inner mitochondrial membrane stability, and contributed to a decrease in antioxidant production (Hagen et al.,
N,N'-bis (2-mercaptoethyl) isophthalamide acts as an antioxidant and heavy metal chelator (Secor et al.,
Antisplicing oligonucleotides are a method of ribonucleic acid modulation and are increasingly being used to regulate protein expression in a multitude of diseases (i.e., from Alzheimer's disease to progressive supranuclear palsy, targeting tau). Antisplicing oligonucleotides (ASOs) inhibit tau accumulation and stabilize the hairpin RNA structure (Boxer et al.,
There is only one registered clinical trial investigating the safety, tolerability, and pharmacokinetic parameters of the intrathecally administered ASO called NIO752 in patients with progressive supranuclear palsy (NCT04539041). This trial will assess the adverse effects NIO752 and occurrence of suicidal behaviors by CSF sampling. The study has already started recruiting participants, but finalization of the trial is estimated to be October 17, 2023 (US National Library of Medicine,
Hairpin short-interfering RNA (siRNA) inhibits both 3α- glycogen synthase kinase and 3β-glycogen synthase kinase (GSK-3α and GSK-3β), resulting in increased levels of β-catenin (Yu et al.,
Defects in mitochondrial DNA can lead to disruption of the electron transport chain and exacerbation of oxidative stress, which contributes to increased activity of kinase pathways (Swerdlow et al.,
Phosphorylated endoplasmic reticulum kinase (PERK) controls cellular response against unfolded or incorrectly folded proteins. Immunostaining studies have described a type of p62 and ubiquitin-positive aggregates, where p62 is a marker of autophagy dysfunction. Vesicles containing p62, ubiquitin, and microtubule-associated proteins 1A/1B light chain 3B (LC3) are evidence of lysosomal impairment (Bruch et al.,
Both
Rho-associated coiled-coil-containing protein kinases 1 and 2 (ROCK 1/2) are serine/threonine kinases involved in cellular motility (Riento and Ridley,
Another approach, based on genetic modifications, is altering the chemical structure of the tau protein. Studies focusing on traumatic brain injury (TBI), known as a risk factor for chronic traumatic encephalopathy (CTE) and AD, showed that neuronal damage results in an increased ratio of the cis-form of tau, which impairs axonal transport and leads to apoptosis. The whole phenomenon was called “cistauosis” (Kondo et al.,
As shown previously, the activity of peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) protein is decreased in AD. Thus, the upregulation of this protein may be considered as a potential target for tauopathy treatment (Kondo et al.,
There are several candidate compounds analyzed in preclinical studies in order to effectively block tau phosphorylation, e.g., brain-specific calpain inhibitor and serine/threonine protein kinase 5 (CDK5) (Tyer and Hill,
CDK5 is involved in the regulation of the cell cycle and supports the creation of new synapses and vessels (Riento and Ridley,
Blocking β-
ASN120290, an inhibitor of O-GlcNAcase, was assessed in pre-clinical and clinical trials. In mice carrying P301L tau mutation, the inhibition of more than 80% of O-GlcNAcase activity led to a measurable increase in O-GlcNAcylated proteins in the brain (Hastings et al.,
By magnetic resonance imaging, it was found that MK-8719, another O-GlcNAcase inhibitor, reduced tau aggregates and forebrain atrophy in transgenic tau rTg4510 mice (Wang et al.,
One of the kinases associated with increased levels of tau deposits, not only in progressive supranuclear palsy but also in corticobasal degeneration and Alzheimer's disease, is GSK-3 (Ferrer et al.,
Tideglusib (NP031112, NP12) is a GSK-3β inhibitor registered as an orphan drug by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) (Medina,
Studies have also considered indirect mechanisms of GSK-3 inactivation that may lead to stem cell proliferation (Nedachi et al.,
AZP2006, a drug currently in phase 2 clinical trials, is a small, multifunctional molecule that stabilizes the progranulin-prosaposin complex and increases progranulin concentration [ALZFORUM. (
Another potential therapeutic progressive supranuclear palsy target is the Src family kinase member Fyn. This non-tyrosine receptor kinase is associated with the regulation of the inflammatory processes, neuronal development, and cancer development (Schenone et al.,
Methylthioninum chloride (methylene blue [MB], TRx0014) is a phenothiazine with known anti-tau accumulation activity used in both
Nilotinib (AMN107) is an oral drug classified as a c-Abl tyrosine kinase inhibitor group, primarily used in Philadelphia chromosome-positive chronic myeloid leukemia (CML) treatment (Kantarjian et al.,
The second potential therapeutic approach in tauopathies is the activation of proteasomes. Inhibitors of phosphodiesterases (iPDEs) have proven to be neuroprotective (Kumar and Khanna,
Recent trials have shown other encouraging results, indicating, apart from the decreased accumulation of misfolded tau protein, anti-inflammatory effects after the application of rolipram, a selective PDE-4 inhibitor (Zhu et al.,
There are also drugs suspected to stabilize microtubules via specific mechanisms. This group includes neomycin (aminoglicoside antibiotic regulating exon 10 splicing but not demonstrating enough selectivity) (Varani et al.,
TPI-287, part of the taxoid family, is a tubule-binding and microtubule-stabilizing molecule. The clinical trial, which was conducted simultaneously with a group of patients with AD, investigated the safety and tolerability of TPI-287 administration in patients with primary four repeat tauopathies (4RT), PSP, and CBS by the intravenous infusion of TPI-287 in three cohorts (Sakamoto et al.,
Another compound demonstrating a similar mechanism of action is epothilone D (BMS-241027), a microtubule stabilizing agent with the ability to pass through the BBB (US National Library of Medicine,
Dictyostatin is also considered as a potential option in future tauopathy treatment. Dictyostatin is a macrolide with microtubule-stabilizing and anticancer properties (Paterson et al.,
Since progressive supranuclear palsy is not only considered as a disease of the central nervous system, it seems crucial to explore cells that are not strictly connected with the nervous system. For that purpose, studies have examined mesenchymal stromal cells (MSCs) obtained from patients with PSP (Calogero et al.,
Mesenchymal stromal cells can differentiate into cells of every germinal layer: ecto-, endo-, and mesoderm, whereas brain-derived neurotrophic factor (BDNF) and retinoic acid (RA) induce the transformation of MSCs into neuronal cells (Anghileri et al.,
Studies in a transgenic Alzheimer's disease mouse model showed that the injection of human adipose derived stem cells (hASCs) significantly increased the level of anti-inflammatory interleukin-10, suggesting the neuroprotective effect of hASCs. This manipulation also increased the concentration of the postsynaptic density protein-95 (PSD-95) as well as synaptophysin, markers indicating synaptic and dendritic stabilization (Kim et al.,
Stem cells are an active area of clinical research, and there have been several PSP clinical trials with promising results. Those studies demonstrate the safety of intraarterial MSC administration in patients with PSP and suggest that while clinical stabilization is possible, it may be disappointingly temporary compared with expectations (US National Library of Medicine,
Another origin of mesenchymal stromal cells could be adipose tissue; the first case of a therapy using this cell source was described in South Korea in 2014 (Choi et al.,
A future study analyzing stem cell administration is currently recruiting participants. It plans to transfer bone marrow stem cells (BMSCs) to the vascular system and to the nasal cavity, with the premise that the branches of the trigeminal nerve located in conches and meatuses will allow stem cells to enter the CSF (US National Library of Medicine,
There is an increasing interest in developing molecule-specific antibodies, since neutralization of tau aggregates seems to be a crucial step in progressive supranuclear palsy treatment, and novel trials are suspected to bring positive results. On one hand, the intracellular nature of tau limited the pursuit of immunotherapy usage in patients with tau pathologies (Avila,
The liposome-based amyloid vaccine (ACI-35) has had a significant effect on a P301L tau transgenic mouse mode, not only in short-term evaluation by the sudden expression of specific tau-antibodies but also in general improvement of motor impairment in comparison with the control group (US National Library of Medicine,
Armanezumab is a monoclonal, humanized antibody that targets the N-terminal region of the tau protein, called the “phosphatase activation domain”. When tau is pathologically accumulated, its N-terminal region, normally hidden in a “paperclip” shape, becomes visible and plays a significant role in tau propagation. Studies on tau transgenic mice demonstrated the therapeutic activity of armanezumab, shown by decreased levels of tau spread, aggregation, and toxicity with simultaneously high specificity (Agadjanyan et al.,
AV-1980D is an anti-tau deoxyribonucleic acid vaccine acting against the same epitope as armanezumab (Davtyan et al.,
AADvac1 is a form of an active vaccine, the production of which was based on the specific fragment causing tau oligomerization (Shoeibi et al.,
Antibodies against the microtubule binding domain (MTBD) may also be potentially useful in the treatment of progressive supranuclear palsy. Recently published data show the effectiveness of injections of such antibodies. These results showed a high affinity for tau and responses against tau aggregates in a mouse model (Croft et al.,
The BIIB092 investigation in progressive supranuclear palsy (PASSPORT) was evaluated in a TauBasket trial, which included patients with corticobasal degeneration, frontotemporal dementia (FTLD), traumatic encephalopathy syndrome (TES), symptomatic MAPT (sMAPT) mutation carriers, and progressive nonfluent aphasia (ALZFORUM,
Corticobasal degeneration is a form of atypical parkinsonism histopathologically characterized by aggregates of tau protein with four microtubule-binding repeats similar to those observed in progressive supranuclear palsy (Reich and Grill,
The causes of corticobasal degeneration are currently unclear. The H1-haplotype of the MAPT gene expressed in CBD and PSP is one of them (Houlden et al.,
The prevalence of progressive supranuclear palsy, corticobasal syndrome, and frontotemporal dementia is estimated to be 10.8/100,000. Their incidence index does not diverge remarkably from mortality (Coyle-Gilchrist et al.,
Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS): Summary of emerging novel therapies.
Inflammation modulation | 5-lipooxygenase (5-LO) | Pre-Clin | Completed | Overexpression of 5-LO gene showed enhanced amyloid-β (Aβ) aggregation | Boxer et al., |
5-lipooxygenase (5-LO) | Pre-Clin | Completed | 5-LO block led to decreased tau levels and memory improvement | US National Library of Medicine, |
|
Benfotiamine (BFT) | Pre-Clin | Completed | BFT reduced the level of MAPT and amyloid plaques | Färber and Kettenmann, |
|
Benfotiamine (BFT) | Pre-Clin | Completed | BFT reduced the level of glycated tau and improved mice behavior | Maphis et al., |
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Benfotiamine (BFT) | Pre-Clin | Completed | BFT considered as a anti-inflammatory and neuroprotective factor | Chu et al., |
|
Tolfenamic acid (TA) | Pre-Clin | Completed | TA reduces the total tau-distributionin mice central nervous systems | Marras et al., |
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Tolfenamic acid (TA) | IIa | Not yet recruiting | Safety and tolerance of tolfenamic acid in individuals with PSP; CSF evaluation | Tapias et al., |
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Modulation of oxidative stress | PERK activation | Pre-Clin | Completed | Reduction of 4R-tau level and tau phosphorylation | Chirichigno et al., |
PERK activation | Pre-Clin | Completed | Improvement of motor and cognitive functions, decreased tau phosphorylation | Chirichigno et al., |
|
SLC25A38/Appoptosin regulation | Pre-Clin | Completed | Increased level of Appoptosin is connected with tau clevage and motor functions impairment | Zhao et al., |
|
Coenzyme Q10 | II | Completed | Gentle improvement of PSP symptoms measured by PSPRS and FAB | Stamelou et al., |
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Coenzyme Q10 | Clinical | Completed | Primary outcome measures: efficacy of Coenzyme Q10 UPDRS and PSPRS; no significant results | Apetauerova et al., |
|
Creatine, pyruvate, niacinamide | Clinical | Completed | Primary outcome measures: clinical features of PSP, including motor function, neuropsychological function, and blood chemistry; results were not published | US National Library of Medicine, |
|
α-lipoic acid and L-acetyl carnitine | Pre-Clin | Completed | α-lipoic acid and L-acetyl carnitine have a neuroprotective effect | DeVos et al., |
|
α-lipoic acid and L-acetyl carnitine | II | Completed | Primary outcome measures: incidence and severity of adverse events: the most common adverse effects were: restlessness, seizures, insomnia and dizziness | DeVos et al., |
|
-lipoic acid and L-acetyl carnitine | Pre-Clin | Completed | ALCAR led to induction of mitochondrial restoration and was convinced to present anti-oxidative properties | DeVos et al., |
|
NBMI - N,N'-bis (2-mercaptoethyl) isophthalamide | IIa | Recruiting | Primary goal is to evaluate NMBI influence on motor, non-motor syndromes and check the QoL index in PSP and MSA patients | MacDonald et al., |
|
RNA modulation | ASO | Pre-Clin | Completed | ASO reduced tau mRNA and protein in the brain, spinal cord, and CSF | Ferrer et al., |
ASO | Pre-Clin | Completed | ASO reduced the severity of seizures observed in these models | Iqbal et al., |
|
ASO | I | Recruiting | Primary outcome measures: number of adverse effects, change in severity scores for C-SSRS and levels of infection indicators in CSF | Bruch et al., |
|
siRNA | Completed | siRNA leads to GSK3α and GSK3βinhibition | Yuan et al., |
||
Kinases and enzymes modulation | ROCK inhibition | II | Recruiting | Primary outcome measures: number of adverse effects assessed in psychical examination, imaging and laboratory tests | Bruch et al., |
Pin1 inhibition | Pre-Clin | Completed | Inhibition of cis-trans cover; antibodies used against cis-form prevented from tauopathy development | Riento and Ridley, |
|
CDK5/BAG3/Hsp70 path targeting | Completed | BAG3 loss resulted in loss of memory functions and disruption of neuronal homeostasis | Silva and Haggarty, |
||
O-GlcNAcase inhibitor | Pre-Clin | Completed | Wells et al., |
||
ASN120290 (O-GlcNAcase inhibition) | I | Completed | Drug remained safe and well-tolerated | Yuzwa et al., |
|
ASN120290 (O-GlcNAcase inhibition) | I | Recruiting? | Main goal of trial is to calculate OGlcNAcase enzyme occupancy by ASN120290 in CSF | Chen et al., |
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MK-8719 | Pre-Clin | Completed | Reduction of tau aggregates and diminishment of forebrain atrophy | Hastings et al., |
|
MK-8719 | I | Completed | Drug was well-tolerated and its level was proportional with the dose | ALZFORUM. ( |
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GSK-3β hemi-knockout | Pre-Clin | Completed | Decrease of GSK-3β leads to inhibition of tau phosphorylation and aggregation | Ferrer et al., |
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Tideglusib (NP031112, NP12) | Clinical | Completed | Tideglusib was acclaimed as safe, although trial showed also no significant changes between drug intake or placebo both in primary and secondary outcomes | Serenó et al., |
|
AZP2006 | II | Recruiting | Primary outcome measures: tolerability, safety, pharmacokinetics and effect of AZP2006; it also includes CSF markers evaluation | Mendsaikhan et al., |
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Methylene blue, TRx0014 | Pre-Clin | Completed | MB reduced tau pathology and inflammation, it also showed improvement in mice behavior | van Dyck et al., |
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Methylene blue, TRx0014 | II | Completed | Benefit was seen on the ADAS-cog scale in both mild and moderate subjects | van Dyck et al., |
|
Enhancement of abnormal proteins removal | Nilotinib (AMN107) | Pre-Clin | Completed | Treatment led to decreased level of tau aggregates and improvement in motor symptoms | National Cancer Institute, |
Rolipram (PDEs inhibitor) | Completed | Rolipram is suspected to decrease level of inflammation in CNS, although it has different biological effects | Lokireddy et al., |
||
Sildenafil (PDE-5 inhibitor) | I | Completed | Enhanced ability to focus attention and select relevant target stimuli in the sildenafil condition; further studies are being required | García-Osta et al., |
|
Microtubules stabilization | TPI-287 | I | Completed | Trial showed decreased chitinase-3-like protein-1 (YKL-40) levels in the 4RT arm, what presumably evidenced reduction of inflammation due to TPI-287 administration | Schultheiss et al., |
Epothilone D (BMS-241027) | PreClin | Completed | Drug reduces the amount of cerebral pathologic tau and also inhibits axonal destruction, concomitantly contributing to the axonal transport improvement | Zheng et al., |
|
Dictyostatin | Pre-Clin | Completed | Low doses infusion showed decrease of hippocampal CA3-neurons atrophy and lowered the level of mature-tau markers | Zheng et al., |
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Stem cells administration | hASCs | Pre-Clin | Completed | hASCs significantly decrease the level of inflammation and indicates synaptic and dendritic stabilization | Lin et al., |
BMSCs | II | Completed | Almost all treated patients were alive after one year cell infusion, the motor function rating scales remained stable for at least six-months | Chao et al., |
|
AdMSCs | Human study performed on one patient in South Korea using MSCs obtained from adipose tissue | Completed | No serious adverse effects, significant reduction in PSPRS, strength and speed of activities performed with upper limbs have also improved | Schneider and Mandelkow, |
|
BMSCs | Clinical | Recruiting | Primary outcome measures: Activities of Daily Living (ADL) | Höglinger et al., |
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Specific antibodies | ACI-35 vaccine | Pre-Clin | Completed | Sudden expression of specific tau-antibodies, general improvement of motor impairment compared to the placebo group | Edemekong et al., |
ACI-35.030 vaccine | Clinical | Last stage of trial, evaluating effect of the highest vaccine dose is planned to be finished in 2023 | Significant change in IgG-antibodies titers and did not cause adverse effects | Clavaguera et al., |
|
Armanezumab | Pre-Clin | Completed | Decreased level of tau scattering, aggregation and toxicity with simultaneously high specificity | Canesi et al., |
|
AV-1980D | Pre-Clin | Completed | Strong humoral reaction resulting in antibodies production | Theunis et al., |
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AV-1959R and AV-1980R | Pre-Clin | Completed | High affinity of antibodies and significant reduction of tau aggregates | US National Library of Medicine, |
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Bepranemab (UCB0107) | I | Completed | All participants had completed the study, there were no serious adverse effects | ALZFORUM, |
|
AADvac1 | Pre-Clin | Completed | Proved AADvac1 safety profile and exhibited its positive influence on clinical disease symptoms | AC Immune, |
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AADvac1 | II | Completed | AADvac1 is safe and presents accurate immunogenicity | UCB, |
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Antibodies against microtubule binding domain (MTBD) | Pre-Clin | Completed | All of the new tau antibodies detected human tau in whole brain lysates from PS19 mice | US National Library of Medicine, |
|
BIIB092 (gosuranemab) | I | Terminated | Primary outcome measures: incidence of Treatment-Emergent Adverse Events | Axon Neuroscience, |
Multiple system atrophy is a fatal neurodegenerative disease characterized by rapid progression and low life expectancy. Mean survival rate is estimated to be 6–10 years (Monzio Compagnoni and Di Fonzo,
Multiple system atrophy, as one of the synucleinopathies, is characterized by pathological accumulation and aggregation of α-synuclein mainly in the cytoplasm of oligodendroglia cells (Monzio Compagnoni and Di Fonzo,
α-Synuclein, a product of the alpha-synuclein (SNCA) gene (Kisos et al.,
Studies with an MSA mouse model showed Anle 138b, an oral general inhibitor of protein aggregation, to be successful in reducing oligomeric α-synuclein concentration and glial cytoplasmic inclusions. This leads to improvement of motor function in Anle 138b-treated mice compared with controls (Wagner et al.,
The mammalian target of rapamycin kinase signaling pathway is widely known for its role in controlling cell metabolism and stimulating cell proliferation. It is also a suppressor of catabolic pathways and a promotor of anabolic ones, such as protein and lipid synthesis (Kim and Guan,
The administration of epigallocatechin gallate (EGCG), a polyphenol found in green tea, was also evaluated as a possible anti-aggregation approach. Preclinical trials with mouse models showed that EGCG inhibited α-synuclein aggregation and reduced its toxicity. Unfortunately, the phase 3 clinical placebo-controlled trial showed no improvement in disease progression (Levin et al.,
Several studies have shown that impairment of the ubiquitin-proteasome system (UPS) contributes to the pathogenesis of synucleinopathies such as Parkinson's disease or multiple system atrophy (Tanji et al.,
Active immunization, to induce a long-lasting antibody response, may reduce α-synuclein aggregation. Antibodies are believed to increase alpha-synuclein destruction and, therefore, inhibit its aggregation in oligodendrocytes. PD01 and PD03 peptide vaccines consist of short amino acid sequences that are complementary to a segment of α-synuclein. The short peptides are bound to the carrier protein recognized by T-helper cells and help to develop a long-lasting immune response. Studies conducted on transgenic mice have shown that administration of PD01 vaccine, which mimics the C-terminal peptide of α-synuclein, induced a specific immune response against α-synuclein through production of antibodies. This response reduced α-synuclein accumulation in glial cells and decreased demyelination in both the neocortex and striatum. Improved motor skills were also observed in PD01-treated mice (Mandler et al.,
Another possible strategy is passive immunization with specific α-synuclein-targeting antibodies. Preclinical trials showed that injections of anti-α-synuclein antibody in transgenic mice resulted in a decrease in α-synuclein accumulation in spinal cord and hippocampus and lowered GCI concentration in oligodendroglia (Kallab et al.,
Recently, another potential therapeutic pathway for addressing neuronal loss has been developed using autologous mesenchymal stem cells (MSCs) in multiple system atrophy and other parkinsonian syndromes therapy (Shin and Lee,
Studies on mouse models and patients with multiple system atrophy showed insulin resistance in oligodendrocytes and neurons of the putamen and impairment of insulin/IGF-1 signaling. These changes may affect the functioning of oligodendrocytes and result in neurodegeneration in the putamen (Bassil et al.,
Decreased levels of neurotrophic factors such as glial derived neurotrophic factor (GDNF), brain derived neurotrophic factor (BDNF), and insulin-like growth factor 1 (IGF1) have been identified in human brains with multiple system atrophy and in mouse models (Ubhi et al.,
Studies on transgenic mice have recently shown that FTY720-Mitox, a derivative of the FTY72 drug approved for multiple sclerosis, increased oligodendroglia GDNF mRNA and protein. FTY720-Mitox acted by suppressing the downregulation of GDNF expression, which is seen in MSA brain. Simultaneously, FTY720-Mitox administration resulted in lowered α-synuclein aggregation in the spinal cord and reduced microglial activation in the cerebellum. These effects coincided with improved motor skills and sweat function, an indicator of dysautonomia. Furthermore, FTY720-Mitox also acted as mitochondria protector, which is extremely promising, taking into consideration the possible role of mitochondrial dysfunction in MSA pathogenesis (Vidal-Martinez et al.,
Oxidative stress due to mitochondrial impairment plays a significant role in the pathogenesis of progressive supranuclear palsy.
Myeloperoxidase is an enzyme that acts in neutrophiles, eosinophiles, and monocytes. It is involved in the production of reactive nitrogen and oxygen species and is a mediator of inflammatory processes in many diseases (Aratani,
Multiple system atrophy (MSA): Summary of emerging novel therapies.
Inhibition of a- synuclein aggregation | Anle 138b | Pre-Clin | Completed | PLP-hαSyn mice show motor improvement, preservation of dopaminergic neurons, decreased microglial activation | Houlden et al., |
Anle 138b | I | Active | |||
Sirolimus (oral) | II | Terminated | Difference in UMSARS score between placebo and treated group | Dickson, |
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EGCG | III | Completed | No improvement in the progression of the disease | Gilman et al., |
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Microtubule depolymerizing agent (Nocodazol) | Pre-Clin | Completed | Suppression of α-synuclein accumulation in mice models | Schapira, |
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Immunization | PD01 | Pre-Clin | Completed | Prevention of demyelination in neocortex and striatum, production of specific antibodies, motor improvement in transgenic mice | Surguchev and Surguchov, |
PD01; PD03 | I | Completed | Significant sustained antibody IgG response against PDO1 and PD03, therapy safe and well-tolerable | Watts et al., |
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anti-α-synuclein antibody | Pre-Clin | Completed | Suppression of α-synuclein intracellular accumulation in spinal cord and hippocampus, lowered GCIs concentration in oligodendroglia | Djelloul et al., |
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Stem cell therapies | hMSC injection | Pre-Clin | Completed | Prevention of neuronal loss in striatum, motor improvement in hMSC treated mice | Burré, |
hMSC intraarterial/intravenous administration | II | Completed | Suppression of disease progression assessed by UMSARS score | Wagner et al., |
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autologous hMSC intravenous administration | I | Completed | Proved to be safe and well-tolerated | Heras-Garvin et al., |
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autologous hMSC intravenous administration | Phase I follow up | Active | Aims to conduct long term follow up of the patients who took part in phase I | US National Library of Medicine, |
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intrathecal administration of hMSC | I/II | Completed | Proved to be safe and well-tolerated, suppression of disease progression assessed with UMSARS score | Kim and Guan, |
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Addressing insulin resistance | Intranasal insulin | II | Completed | Improved cognitive and motor performance in treated patients | US National Library of Medicine, |
Exendin-4 subcutanous administration | Pre-Clin | Completed | Lowered insulin resistance and decreased monomeric α-synuclein level in striatum | Lopez-Cuina et al., |
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GLP-1 analog | II | Active | Change in UMSARS score between placebo and treated group, assessment of safety and tolerability | Tanji et al., |
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Increasing neurotrophic factor levels | GDNF infusion | Pre-Clin | Completed | Attenuation of motor deficits, alleviation of neuropathological process | Stefanova et al., |
Fluoxetine | Pre-Clin | Completed | Improvement of motor skills in transgenic mice and decreased neurodegeneration in neocortex and hippocampus | Mandler et al., |
|
GDNF gene infusion into putamen | I | Active | Change in UMSARS score between placebo and treated group, incidence of treatment adverse effects and serious adverse effects, change in quality of life | Meissner et al., |
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FTY720-Mitoxy | Pre-Clin | Completed | Motor skills and sweat function improvement, lowered α-synuclein aggregation in spinal cord | US National Library of Medicine, |
|
Fighting oxidative stress (mitochondrial dysfunction) | inosine 5′-monophosphate | II | Completed | Improvement in cognitive function assessed with MoCA and MMSE in comparison with placebo group | Caplan and Dennis, |
Reducing neuroinflammation | MPO inhibitor | Pre-Clin | Improvement of motor skills in transgenic mice model concomitant with reduction of neuroinflammation and activation of microglia in striatum | Stemberger et al., |
|
Verdiperstat | III | Change in UMSARS score between placebo and treated group, change in quality of life, assessment of safety and tolerability | Lee et al., |
Progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration, classified as atypical parkinsonian diseases, have only been treated symptomatically so far. Considering all of the recently published information about potential causes and clinical trials targeting candidates involved in disease development, one can hope that treatments addressing both disease symptoms and progression will lead to novel therapeutics and potential cures in the near future.
DP and WM: literature review and manuscript preparation. NM: study design, review of the manuscript, and final acceptance. All authors contributed to the article and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Alzheimer's disease
acetyl-L-carnitine
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
activated protein kinase
atypical parkinsonian syndromes
antisplicing oligonucleotides
activating transcription factor 4
amyloid β
blood brain barrier
brain-derived neurotrophic factor
benfotiamine
bone marrow stem cells
botulinum toxin A
corticobasal degeneration
corticobasal syndrome
cyclin-dependent kinase 5
serine/threonine protein kinase 5
chronic myeloid leukemia
central nervous system
cyclooxygenase-2
cAMP response element binding
cerebrospinal fluid
chronic traumatic encephalopathy
microglial specific fractalkine receptor
epigallocatechin gallate
eukaryotic translation initiation factor
frontal behavioral-spatial syndrome
frontotemporal dementia
frontotemporal lobar degeneration
γ-aminobutyric acid
glial cytoplasmic inclusions
glial derived neurotrophic factor
glial fibrillary acidic protein
glucagon-like peptid 1 analog
glycogen synthase kinase-3α
glycogen synthase kinase-3α and 3β
glycogen synthase kinase-3β
human adipose derived stem cells
heat shock protein 70
insulin-like growth factor 1
interleukin-1 receptor
inhibitors of phosphodiesterases
5-lipooxygenase
leukotrienes
microtubule-associated protein tau
methylene blue
Mini-Mental State Examination
myelin-associated oligodendrocyte basic protein
myeloperoxidase
magnetic resonance imaging
multiple system atrophy with dominant autonomic symptoms
multiple system atrophy with dominant cerebellar symptoms
multiple system atrophy
multiple system atrophy with dominant parkinsonian symptoms
mesenchymal stem cells
microtubule-binding domain
nicotinamide adenine dinucleotide
nicotinamide adenine dinucleotide phosphate
nonfluent variant of primary progressive aphasia
N,N'-bis (2-mercaptoethyl) isophthalamide
neurofilament light chain
N-methyl-D-aspartic acid
Non-Motor Symptoms Scale
neural protein cells
NF-E2-related factor 2 (nuclear factor erythroid 2-related factor 2)/antioxidant responsive element
nonsteroidal antiinflammatory drugs
O-linked β-N-acetylglucosamine
OGA, β-N-acetylglucosaminidase
6-hydroxydopamine
p38-mitogen activated protein kinase
Parkinson's disease
phosphorylated endoplasmic reticulum kinase
positron emission tomography
progranulin gene
cAMP-dependent protein kinase A
protein phosphatase 2A
postsynaptic density protein-95
systemic proteasome suppression
progressive supranuclear palsy
Progressive Supranuclear Palsy Rating Scale
progressive supranuclear palsy like syndrome
retinoic acid
reactive nitrogen species
reactive oxygen species
primary four repeat tauopathies
short-interfering RNA
symptomatic MAPT mutation carriers
tolfenamic acid
traumatic brain injury
traumatic encephalopathy syndrome
toll-like receptor 4
tumor necrosis factor α
uric acid
Unified MSA Rating Scale
unfolded protein response
ubiquitin-proteasome system
chitinase-3-like protein-1.