AD is a progressive neurological condition associated with aging, and is the primary cause of dementia in humans, comprising around 60–80% of cases (Crous-Bou et al., 2017). By 2050, it is estimated that the global incidence of people with AD is set to increase to more than 100 million (Lynch, 2020). AD was first described in 1906; despite decades of study, the molecular basis of AD’s pathogenesis remains a mystery. In contrast, no well-documented therapeutic approaches exists which can slow or arrest the disease’s advancement. Multiple risk factors, such as aging, genetic predisposition, hereditary, occupation, and neurological damage, contributes to AD development (Association, A. S, 2010). AD is defined by developing distinct protein aggregates namely extracellular amyloid-beta (Aβ) plaques formation and intracellular neurofibrillary tangles (NFTs) formation. As the condition worsens, afflicted brain areas succumb to toxic stress, as indicated by massive neuronal death and CNS shrinkage (Querzfurth, 2010). Studies have revealed that autophagy is a primary modulator of Aβ generation and clearance (Nilsson and Saido, 2014). In addition, there is substantial evidence that failure in autophagy process is related to AD and other neurodegenerative disorders which leads towards gradual accumulation of misfolded proteins particularly Aβ aggregates (Oddo et al., 2006). In contrast, in healthy brain tissues, the synthesis of Aβ peptides is substantially lesser compared to the clearance rate, at 7.6 and 8.2% per hour, respectively (Bateman et al., 2006).

Aβ peptides are produced by the autophagosomal cleavage of amyloid precursor protein (APP) during the autophagic changeover of APP-rich organelles. In AD, autophagolysosome development and retrograde trafficking to the neural body are inhibited (Nixon, 2007), resulting in an enormous accumulation of autophagic vacuoles in neural cells. This accumulation might be associated with ESCRT-III malfunction, leading to neurodegeneration (Lee et al., 2007; Yamazaki et al., 2010), and may impair the fusing of autophagosomes with the endo-lysosomal system, hence affecting autophagosome differentiation (Rusten and Stenmark, 2009). The clearance of Aβ from the brain is accomplished by several mechanisms. First, they are susceptible to being destroyed directly by different Aβ-degrading proteases, such as BACE1 and CTSD (Saido and Leissring, 2012). Second, Aβ peptides aggregate in dystrophic neurites (the major elements of neuritic senile plaques in AD), becoming a significant source of the main intracellular pool of lethal peptides (Nixon et al., 2005; Yu et al., 2005). In addition, the recycling route of Aβ peptides is found in the neurons of patients with AD (Nilsson et al., 2013; Nilsson and Saido, 2014). According to a recently published study, neurons produce Aβ peptides in an autophagy-dependent way, and the deposition of intracellular Aβ aggregation is cytotoxic to CNS, enabling the development of AD (Nilsson et al., 2013). In conclusion, defective autophagy is a well-documented pathway in the pathophysiology of Aβ metabolism associated with AD.

AD primarily impacts the hippocampus, amygdala, and other parts of the brain (Association, A. S, 2019). It is commonly thought that Aβ deposition, tau protein NFTs, neurotoxicity, neurovascular dysfunction, and oxidative stress are involved in the etiology of AD (Youdim, 2010; Robinson et al., 2017). Reports have shown that circRNAs accumulate in the brains of aged people, and they are found in higher concentrations in the brains of mammals than in any other tissue (Rybak-Wolf et al., 2015; You et al., 2015). Some circRNAs accrue considerably in the brain subcellular compartments (such as synapses) throughout the course of neuronal ageing compared to their respective mRNAs; as a result, they might be considered as distinct class of ageing biomarkers (Gruner et al., 2016). In addition, ageing-related defective alternative splicing might result in an upsurge in neuronal circRNA biosynthesis (Fletcher et al., 2018). Synapses have the highest amount of circRNAs and their frequency rises with ageing, revealing they are involved in neurodevelopment and synaptic plasticity (Gruner et al., 2016). Various species accumulate circRNA throughout ageing, suggesting it might be a harmful agent for ageing and age-related disorders, likewise AD (Cai et al., 2019; Lo et al., 2020). CircRNAs have been demonstrated to ameliorate AD-like clinical symptoms in cellular and animal models of the disease, highlighting their function in regulating AD progression (Dube et al., 2019).

Extensive research has focused predominantly on circRNAs, and it is becoming apparent that few of them (such as circRNA Cdr1as and circ 000950) act as microRNA sponges, disrupting downstream miRNAs and contributing to the development of neurodegenerative disorders (Piwecka et al., 2017; Wang et al., 2018). In one of the study, authors performed microarray analysis to study the expression pattern of circRNAs in SAMP8 mice (animal model of overproduction of APP and oxidative damage). Results revealed 85 differentially expressed circRNAs. One of the most significantly dysregulated circRNA, mmu_circRNA_017963, was found to be strongly related with autophagosome assembly which reveals possible implication of involvement of autophagy associated circRNA in AD (Figure 2; Huang et al., 2018; Tables 1 and 2).

Accumulation of Aβ proteins is an initial pathological feature of AD, which is exacerbated by the faulty production of APP and the abnormal level of BACE1 (Alcendor, 2020). Research revealed that miR-138 levels in APP/presenilin-1 (PS1) mice increased with age, indicating that miR-138 might decrease disintegrin and metalloproteinase 10 (ADAM10) expression and enhance Aβ synthesis in the mouse model. In addition, AD patients might have reduced levels of circHDAC9, which might boost miR-138 expression and reverse Sirt1 repression and excessive Aβ synthesis generated by miR-138 (Lu et al., 2019). UBE2A, the key effector of the ubiquitin-26 s proteasome system, which regulates the clearing of Aβ by proteolytic cleavage, is yet another mechanism that circRNAs might impact AD. However, it is reported that brains affected by sporadic AD have lower levels of UBE2A, which contributes to the accumulation of Aβ and the production of senile plaque deposits. In a study by Zhao and colleagues, the ciRS-7-miR-7-UBE2A circuit was considerably dysregulated in the neocortex and hippocampus CA1 of individuals with sporadic AD. The considerable reduction in UBE2A expression seemed to be driven by deficiencies in ciRS-7-mediated events, which caused overexpression of miR-7. Additionally, ciRS-7 decreased the proteins APP and BACE1 by enhancing their disintegration via the lysosome and proteasome (Zhao et al., 2016). Furthermore, a 2017 research by Shi and co-authors reported overexpression of the AD-associated sirtuin 7 gene inhibited the translation of the NF-κB while increasing the trafficking of the protein in the cytoplasm, where it promoted degradation of BACE1 and APP (Shi et al., 2017). Bigarré et al. (2021) reported that a rise in the expression levels of circ 0131235 in the middle temporal cortex of individuals with AD might be used as a biomarker for the disease. In addition, it is also hypothesized that enhanced circ 0131235 expressions could be part of a physiologic means to prevent Aβ aggregation (Bigarré et al., 2021).

PD, also known as paralysis agitans is the second most common progressive age-related motoric neurodegenerative disorder that affects approximately 1% of the population over the age of 65 years with a prevalence set to double by 2030 (Aarsland et al., 2021). Loss of dopaminergic neurons in the substantia nigra pars compacta results in slow and insidious cognitive decline along with disabling motor abnormalities including slow movements, tremor, poor balance and rigidity (Junn et al., 2009). It is suggested that circRNAs are important biomolecules for understanding and for addressing the initiation of PD neurodegenerative processes (Hanan et al., 2020). Studies have reported variable expression of circRNAs in the brains of patients with PD, and mounting evidence highlights their possible pathogenic role in PD development (Feng et al., 2020; Hanan et al., 2020; Kong et al., 2021). In one of the study, the authors reported alteration in the expression profiles of six circRNAs in the peripheral blood mononuclear cells obtained from the patients with PD compared with healthy control subjects including circ_0001566, circ_0006916, circ_0000497, circ_0001187, circ_0004368, and circ_0003848 (Ravanidis et al., 2021). One distinguishing feature of PD is the aberrant expression and aggregation of α-synuclein (SNCA), which is found in Lewy bodies. miR-7 has been reported to directly suppress SNCA expression by binding to the 3′ UTR of the SNCA gene and inhibiting its translation. The authors reported decreased expression of miR-7 in the substantia nigra Pars Compacta of patients with PD (McMillan et al., 2017). As circRNA ciRS-7 targets miR-7 (this circRNA contains 63 binding sites for miR-7), it probably serves as an important factor involved in the functioning of neurons as well as a responsible candidate in brain tumour development and neurological disorders (Hansen et al., 2013). Moreover, in another study done on PD, authors reported that clearance of SNCA and its aggregates were facilitated by miR-7 in autophagy dependent manner in differentiated ReNcell VM cells. The authors further revealed that miR-7 increases the formation of LC3 puncta and facilitated the conversion of LC3-I to LC3-II, which indicates increased autophagosome formation (Choi et al., 2018). In addition miRNAs (miR-7, miR-153, miR-214, and miR-133b) which targets SNCA have displayed protective role against the PD models (MPP+/MPTP). The authors revealed that by upregulating SNCA, miR-7 expression is involved in degeneration of the nigrostriatal system in the MPTP-induced neurotoxin model of PD in cultured cells and in mice (Junn et al., 2009). Moreover, miR-7 transfection resulted in more effective SNCA inhibition in the HeLa cell line in the absence of circRNA ciRS-7, showing that ciRS-7 may influence SNCA expression in miR-7-dependent manner, which is also correlated with the pathogenesis of PD (Wang et al., 2021b). In another study circSNCA was shown to sponge miR-7 and up-regulate the production of SNCA mRNA in SH-SY5Y cells, resulting in suppression of autophagy and upregulation of apoptosis (Sang et al., 2018). Authors reported that circSNCA down regulation increased the expression of the autophagy-related protein LC3B-II and the anti-apoptotic protein BCL2, demonstrating the suppression of apoptosis and the promotion of autophagy in PD. The researchers found that after treatment with a dopamine D2/D3 receptor agonist (pramipexole, commonly used in PD therapy), the expression profiles of SNCA and circSNCA were significantly reduced. The authors further reported that the expression of pro-apoptotic genes (CASP3, BAX, PTEN and P53) was reduced as a result of circSNCA downregulation (Sang et al., 2018).

One of the crucial mechanisms of circRNA in disease progression is through its interaction with disease-associated miRNAs (Ghosal et al., 2013). The role of circRNAs as a miRNA sponge in various diseases has also been investigated (Guo et al., 2014). In PD, circRNA zip-2 knockdown led to the reduction of SNCA protein aggregation by sponging miR-60, resulting in better survival outcomes of PD patients (Kumar et al., 2018). In another study authors reported that via sponging miR-7, circRNA s-7 promoted the expression of important genes associated with PD and AD (Lukiw, 2013). Suppressing circHIPK2 expression greatly reduced astrocyte activation through regulating autophagy and endoplasmic reticulum (ER) stress via targeting MIR124–2HG and SIGMAR (Huang et al., 2017a). CircDLGAP4 functions as a molecular sponge in PD patients and competes with MIR134-5p to suppress its activity. It encourages BECN1 and LC3-II expression, which increases autophagy, inhibits apoptosis, and decrease mitochondrial damage (Feng et al., 2020). In PD mouse models, circDLGAP4 is downregulated, which may contribute to the onset of PD by influencing cell viability, apoptosis, mitochondrial damage, and autophagy (Feng et al., 2020). It has been revealed that in PD, circSAMD4A altered the AMPK/mTOR cascade via miR-29c-3p, thus contributing to the death and autophagy of dopaminergic neurons. miR-124 has also been shown to protect dopaminergic neurons in PD via regulating the AMPK/mTOR mediated apoptosis and autophagy (Wang et al., 2021b).

In healthy brain’s substantia nigra, circRNAs accumulate in an age-dependent manner, whereas in the substantia nigra of patients with PD, the total number of circRNAs is reduced due to loss of this connection (Hanan et al., 2020). In one of the study, the authors reported increased expression of circSLC8A1 (this circRNA contains 7 binding sites for miR-128) in the substantia nigra of individuals with PD as well as in oxidative stress model created in cultured cells through Paraquat exposure. Authors further reported that expression profiles of miR-128 targets were also increased in PD individuals (Hanan et al., 2020). Above mentioned data has highlighted the importance of autophagy-associated circRNAs as potential therapeutic targets for PD. Studies of how circRNAs regulate autophagy during PD are still scarce and more investigations are needed.

ALS is a neurodegenerative disease which damages upper and lower motor neurons of the brainstem, and spinal cord, causing paralysis of the voluntary muscles and the death of spinal motor neurons (Brown and Al-Chalabi, 2017; Ramesh and Pandey, 2017). There are number of factors that predispose ALS such as smoking, exposure to chemicals, metals and radiations leading to environmental causes of disease progression (Sutedja et al., 2009). Work done by Zarei et al. suggested that smoking and heavy metal cause mitochondrial damage, glutamate excitotoxicity as well as neurotoxicity (Zarei et al., 2015). Mutations in 40 different genes have been linked with the development of ALS including SOD1, C9ORF72, TARDBP, FUS, OPTN, and TANK-binding kinase 1 (TBK1; Cirulli et al., 2015). Furthermore, mutation in the autophagy pathway genes including p62/SQSTM, OPTN, TBK1, VCP, and C9ORF72 have been reported in ALS patients (Rudnick et al., 2017). The author showed that in both sporadic and familial ALS, mutations in autophagy gene were found. SOD1 was the first gene whose mutations were linked to ALS account accounting for about 3% of total ALS cases with more than 180 mutations discovered thus far linked to ALS (Peggion et al., 2022).

The accumulation of neurotoxic misfolded proteins, inclusions, and aggregates within motor neurons is the primary clinical signature in all cases of ALS. Autophagy has been found to be deregulated in both familial and sporadic cases of the disease (Vicencio et al., 2020). In order to protect the survival of extremely sensitive and specialized neurons, targeting autophagy through pharmacological autophagy-inducing agents has resulted in reduction in disease progression in different in vitro and in vivo models of neurodegenerative diseases (Amin et al., 2020). TBK1 cause the phosphorylation of autophagy adaptors which has a major role in both autophagy and mitophagy (Oakes et al., 2017). The authors showed that ALS causing gene have similar role in the autophagy such as SQSTM1/p62 and OPTN. Mutation in TBK1 lead to impairement of autophagy pathway that lead to accumulation of proteins and lead to pathogensis of ALS (Oakes et al., 2017). Another study by Kwiatkowski et al. revealed that mutation in FUS gene (which plays significant role in autophagy) lead to ALS (Kwiatkowski et al., 2009; Vance et al., 2009). Various atudies have reported shared mechanisms and connections between apparent dysregulations in autophagy and ALS pathophysiology (Nguyen et al., 2019).

CircRNAs are greatly localized in the tissues of human neurons, indicating that they may be significant in the control of the central nervous system (Li et al., 2019a). The study was conducted by Armakola et al. which revealed that deletion of Dbr1 gene which encodes an RNA lariat debranching enzyme was found to significantly lower cytoplasmic TAR DNA-binding protein 43 (TDP-43) toxicity. The main reason is that the lack of the debranching enzyme causes the development of intronic lariats (ciRNA), which bind to TDP-43 and reduce its toxicity (Armakola et al., 2012). Along with TDP-43, a mutation in the RBP known as fused in sarcoma (FUS) is also strongly linked to ALS. Proteins move from the nucleus to the cytoplasm as a result of FUS mutations, which also produce inclusion bodies in the cytoplasm and cause toxicity (Kwiatkowski et al., 2009, Vance et al., 2009). Additionally, FUS not only control the synthesis of circRNA and the introns that flank the back-splicing junctions in N2a cells through their binding (Errichelli et al., 2017). However, the formation of circRNAs (linked to the development of ALS) was shown to be reduced significantly by FUS depletion or its alteration (Verheijen and Pasterkamp, 2017). Another study by D’Amber et al. showed that there is no direct connection between mutant FUS and circ-Hdgfrp3 which is analyzed by post-acquisition and 3D rendering analyses, however circ-Hdgfrp3 is present in FUS-aggregates that connect circ-Hdgfrp3 with the p62/SQSTM1 protein (D'Ambra et al., 2021). These results suggests that it is possible that these granules will eventually be degraded via autophagy. The authors reproted that p62/SQSTM1 has connection with FUS inclusions in the brain and spinal cord of ALS patients (D'Ambra et al., 2021). Furthermore microarray profiling showed that hsa_circ_0023919, hsa_circ_0063411, and hsa_circ_0088036 have significant role in ALS patients (Dolinar et al., 2019). Evidences reported till now revealed that there is a correlation between circRNAs, autophagy and ALS which warrants further in-depth investigations.

Being a protein quality control system, autophagy process is involved in recycling obsolete cellular constituents as well as eliminating protein aggregates and organelles after being damaged. These substrates then reach lysosomes either by delivery within autophagosomes or endosomes. Disruptions caused by these interactions affect neuronal functions, which may cause several neurodegenerative diseases including HD. Studies have shown that autophagy disruption is linked with early cognitive changes in HD and is therefore a potential target for HD treatment (Grosso Jasutkar and Yamamoto, 2021). Furthermore, mutations of autophagy associated genes may specifically increase the risk of HD (Nixon, 2013), which is characterized by psychiatric disturbances cognitive dysfunction, and severe motor dysfunction (Sturrock and Leavitt, 2010). Autophagy associated miRNAs (a type of ncRNA and a target for circRNA) has been reported to be involved in the progression of HD (Choi and Cho, 2021). Expansion of the CAG repeat in the HTT gene is the main causative factor behind HD pathophysiology. In order to identify differentially expressed circRNAs in HD, Marin et al., did microarray analysis of murine cell line model expressing mutant HTT. The authors reported that differentially expressed circRNAs were found to regulate MAPK pathway, Long-term depression pathway as well as dopaminergic synapse which have been previously involved in HD physiopathology (Marfil-Marin et al., 2021). The authors concluded that in-depth understanding of the HD specific circRNA-miRNA-mRNA axis can lead to identify novel biomarkers and potential therapeutic targets for HD. HTT has been previously reported to play a crucial role in selective autophagy, where the loss of the polyQ stretch enhances autophagic capacity in neurons (Zheng et al., 2010). Moreover HTT gene has also found to be structurally similar to selective autophagy proteins known as Atg11, Atg23, and Vac8 (Steffan, 2010). It also promotes autophagy initiation, where as its loss in CNS has been suggested to cause protein accumulation, which might contribute to HD pathogenesis (Gelman et al., 2015). Researchers are still working to find out possible associations and links between autophagic processes and HD pathogenesis (Croce and Yamamoto, 2019). In one of the study, the author identified a circRNA derived from HTT locus in brain districts and in iPS-derived neuronal cell lines. The authors reported that overexpression of the circHTT might cause alteration in the wild-type and mutant HTT expression (Döring et al., 2021). The authors concluded that circRNAs might serve as innovative avenues for therapeutic intervention to treat HD. A number of studies have explored the relationship between neurological disorders, autophagy and circRNAs but association of circRNAs and autophagy with HD is still in infancy and therefore need further studies. In one of the study the authors reported that upregulation of circ016719 expression (which binds miR-29c) in neurons promotes autophagy. Circ016719 ultimately increased the expression of MAP2K6, which then promotes the expression of BECN1, thereby increasing the rate of autophagy in neurons. The authors further reported that circ_016719 knockdown significantly inhibited autophagy (Tang et al., 2020). In another study miR-29c was found among nine miRNAs (miR-128, miR-132, miR-22, miR-218, miR-222, miR-29c, miR-138, miR-344, and miR-674) which were downregulated in YAC128 transgenic mice expressing a full-length mutant HTT (Dong and Cong, 2021). Above mentioned studies supports the notion that circ016719/miR-29c/autophagy axis should be explored in HD models. In another study, upregulation of circHectd1 in astrocytes was found to promote the expression of TIPARP (through miR-142-TIPARP axis), which then induces the expression of LC3-II, thereby activating autophagy (Han et al., 2018). miR-142 has been reported to be linked with HD (Martí et al., 2010) which shows that circHectd1/miR-142/autophagy axis might have implications in HD. In another study circAKAP7 was shown to target miR-155-5p to promote the expression of ATG12, thereby increasing the risk of autophagy (Xu et al., 2020). One of the study reported that in the animal models, overexpression of miR-155 lowered the mutant HTT aggregates in cortex and striatum, as result there was improved performance in behavioral tests (Martinez and Peplow, 2021). A number of other circRNAs might contribute to HD via regulating autophagy such as circLRP1B that inhibits miR-27a-3p, circDLGAP4 that inhibits miR-134-5p, circHIPK2 that inhibits miR-124. We believe that by regulating autophagy, circRNAs might impact the development and/or recovery of HD. However, this hypothesis needs to be confirmed by studying the role of autophagy associated circRNAs in HD development (Wang et al., 2022; Figure 3).

SMA is a devastating genetic neuromuscular condition and the primary cause of infant death, which weakens the muscles resulting in low amounts of the Survival Motor Neuron (SMN) protein (Sansa et al., 2021). There are five types of SMA: Types 0, 1, 2, 3, and 4. SMA 1 (also called Werdnig-Hoffmann disease) is the most common form of the condition, which is deadly within the initial 2 years of life (Park et al., 2010). SMA can appear in a variety of severity levels. Patients with lower spinal cord-motor neuron impairment cause increasing muscle weakness. The SMN protein was given the name “survival motor neuron” because of the apparent importance of protein to the motor system and the finding that the knockout of SMN in mice was embryonically lethal (Schrank et al., 1997). Recent studies have shown that SMN genes generates a huge repertoire of circRNAs through inter-intronic secondary structures (Luo et al., 2022; Singh et al., 2022). There are four subtypes of SMN circRNAs namely Type 1, 2, 3 and 4 circRNAs (Ottesen and Singh, 2020). Most of the SMA data has been generated using SMA mouse models which have confirmed the significant function of autophagy during SMA. In particular, SMA is caused through oxidative stress which increases expression of a mutated superoxide dismutase protein (SODG93A) by triggering autophagy (Dobrowolny et al., 2008). Studies have shown that ncRNAs including circRNAs could be potentially exploited for developing additional SMA therapies (Singh et al., 2020). Research has indicated that autophagy is disrupted during the initial regulatory stages in SMA. The role of circRNAs in SMA pathogenesis is still in initial phases.

miRNAs which are the targets of circRNAs have been exploited in SMA and reports have revealed their neuroprotective abilities (Gandhi et al., 2021). A number of miRNAs including miR-23a (reduced the motor neuron death, increased the motor neuron size as well as muscle fiber area), miR-375 (protects the neuron from apoptosis by inhibiting the tumour suppressor gene p53), miR-9 (crucial modulator associated with SMA severity), miR-146a (regulates crucial signaling pathways in motor neurons), miR-183 (increases the motor neurons survival and improves the motor function of mice with mutant SMN), miR-206 (role in survival endogenous mechanism), and miR-431 (rescue the motor neuron neurite length phenotype through targeting chondrolectin) have been considered as potential therapeutic ncRNAs for treating SMA (Gandhi et al., 2021). These miRNAs have been implicated in autophagy as well as targets of circRNAs in separate studies which warrants further investigations of circRNAs/miRNAs/autophagy axis in SMA (Chang et al., 2012; Zhang et al., 2015; Si et al., 2018; Huang et al., 2019; Shang et al., 2021; Wei et al., 2021).

FRDA, a multi-system, autosomal recessive neurodegenerative disorder and is the most abundantly existing type of hereditary ataxia (Keita et al., 2022). This illness usually starts before the age of 25 with subsequent disease progression including dorsal root ganglia, sensory peripheral nerves, corticospinal tracts, and dentate nuclei of the cerebellum (Santos et al., 2010). Apart from these indications, a very high percentage of patients also advance to hypertrophic cardiomyopathy leading to lower life expectancy. FRDA is caused by the loss of function mutations in FXN gene which is responsible for causing FRDA. FXN gene (9q13-21) actually encodes for Frataxin protein, that is a small protein (210-amino-acids in length) produced as a precursor polypeptide and later exported to mitochondria where proteolytic cleavage occurs to produce the mature type called as m-FXN (Campuzano et al., 1996; Koutnikova et al., 1997; Priller et al., 1997; Schmucker et al., 2008). It is mainly initiated by a homozygous GAA repeat expansion mutation within the intron 1 of the FXN gene (Campuzano et al., 1996). Some of patients are also heterozygous, having one pathogenic mutation (insertion, deletion, point mutation) in one of the FXN allele while having the GAA repeat expansion on the other making them compound heterozygous (Santos et al., 2010). Such expansion in FXN genes develop repeat-dependent epigenetic silencing signals, including repressive histone marks and DNA hypermethylation, that are mostly present in intronic region (Greene et al., 2007). This results in almost 30% reduced production of protein frataxin in the body, consequently, reduced import into mitochondria and reduced mitochondrial functioning, leading to subsequent oxidative stress and cell death.

Studies have reported that autophagy has a crucial role in all neurodegenerative diseases including FRDA. Many experiments have been performed on various cell lines and models to decipher the exact role and mechanism of FRDA and the role of autophagy in its pathogenesis. It is yet to be clarified whether increase in FRDA associated autophagy is a neurodegenerative mechanism (Simon et al., 2004) or it may serve a protective role against stress (Bolinches-Amoros et al., 2014). In one set of experiments, Caenorhabditis elegans (C. elegans) was used as a model organism revealing that a complete knock-out of the frataxin ortholog (frh-1) or severe insufficiency of additional nuclear-encoded mitochondrial respiratory chain (MRC) proteins results in pathological phenotypes such as shorter lifespan and arrested development (Rea et al., 2007). Inversely, partial suppression of this gene, as well as frh-1, results in activation of some beneficial adaptive responses leading to life span extension (Torgovnick et al., 2010). It is also observed that FXN protein expression must be considerably reduced to activate autophagy, which results in reducing lipid content and extended lifespan and in C. elegans. There might exist a causal connection among initiation of autophagy and extended lifespan subsequent to reduced FXN protein expression. This might provide a rationale to further investigate autophagy in the pathogenesis and treatment of FRDA.

In one of the experiment, the authors used gene silencing in human neuroblastoma cell line, SH-SY5Y, to reveal effects on cellular and mitochondrial functioning due to FXN protein deficiency (Bolinches-Amoros et al., 2014). Neuroblastoma is actually a tumor made from the neural crest, like DRG neurons that’s why neuroblastoma cell line seems a better cellular model to study ataxia and other related disorders. The authors observed that the silencing of FXN gene caused mitochondrial dysfunction leading to cellular senescence and an increase in autophagy. However, the authors argue that the induced autophagy might play a protective role in FRDA. Actually neurons are post mitotic cells whose survival is dependent upon autophagy (Lee, 2009). On the other hand, the senescence phenotype observed can be linked to degeneration observed in the FRDA patients. Collectively, possibility exists that autophagy is initiated to protect FXN-deficient DRG neurons from stress, but then again observed degeneration might be because of induction of additional pathways in response to various stresses such as oxidative stress. The discovery of the Drosophila FXN ortholog, fh, (Cañizares et al., 2000) led to the development of fly models of FRDA that can be used to explore FXN function (Calap-Quintana et al., 2015). Experiments conducted using Drosophila model of FRDA, suggested that autophagy is undeniably essential for the shielding effect of rapamycin in hyperoxia (Calap-Quintana et al., 2015).

There are several theories proposed, on the basis of growing evidence, of circRNA role in neurological diseases. Firstly, it is postulated that all RNA molecules, both non-coding as well as protein-coding RNAs communicate with and co-regulate each other by competing for binding to shared miRNAs (Salmena et al., 2011). This hypothesis collectively refers to all RNAs as ceRNA (competitive endogenous RNAs; Salmena et al., 2011). Importantly, there is mounting data that suggests that the RNA communication system (ceRNA) is disrupted in these diseases resulting in a pathogenic state. With reference to FRDA, we can observe that the nuclear production of precursor FXN protein to its mature delivery to mitochondria, highly depends on such interconnected regulation among ceRNAs including circRNAs. Secondly, it has been also suggested that such communication between RNA molecules may play an important role in several repeat-associated diseases including FRDA. FRDA, as already discussed, is mainly caused by homozygous GAA repeat expansion mutations in intron 1. There is a strong argument in Myotonic dystrophy type 1 disease, which is also caused by CTG repeats in the 3′ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene (Brook et al., 1992). The expression of mutation-containing transcripts causes the sequestration of muscle blind-like (MBNL) proteins which normally regulate alternative splicing of pre-messenger RNAs (pre-mRNAs) encoding proteins critical for skeletal, cardiac, and nervous system function (Miller et al., 2000; Pascual et al., 2006). Thus, their sequestration and functional inadequacy results in an aberrant alternative splicing of many target genes. One of the study suggested a role of MBNLs in the production of circRNAs (Ashwal-Fluss et al., 2014). The production of circRNAs might ensue both post-transcriptionally and co-transcriptionally (Wilusz and Sharp, 2013; Ashwal-Fluss et al., 2014; Kramer et al., 2015). Also, their biogenesis competes with the production of linear transcripts (mRNA). Apart from this phenomenon, two other important roles have been proposed of circRNAs which might play a crucial role in pathogenesis of FRDA including contribution in protein and/or RNA transport (Memczak et al., 2013) and regulation of the synaptic functions in neural tissue (You et al., 2015).

There are several studies which have deciphered the role of miRNAs in FRDA. CircRNAs act as sponges for these miRNAs extending their role in the pathogenesis by effecting the key molecules involved in the autophagy associated pathways thereby regulating the biological functions of these cells. For example, those miRNAs targeting mTOR and AMPK pathway might play a crucial role in the progression of FRDA. One such example is hsa-miR223-3p, which is slightly upregulated in FRDA patients (Seco-Cervera et al., 2017; Quatrana et al., 2022). This miRNA is known to be inversely associated with HCLS1 associated protein X-1 (HAX-1). It has been found that Hax-1 plays an important role in the development of the central nervous system and in the pathophysiology of some neurological diseases. The anti-apoptotic protein HAX-1 has been proposed to modulate mitochondrial membrane potential, calcium signaling and actin remodeling (Dong et al., 2022). It is possible that this miRNA might negatively regulate HAX-1 protein thus reducing the anti-apoptotic effect and in turn promotes autophagy in FRDA patients. Another miRNA hsa-miR-886-3p (miR-886-3p) was observed to be upregulated in FRDA patient’s cells as well as peripheral patient’s blood samples (Dantham et al., 2018). The study identified significant deregulation of following miRNAs; hsa-miR-15a-5p, hsa-miR-26a-5p, hsa-miR-29a-3p, hsa-miR-223–3p, hsa-24–3p, and hsa-miR-21–5p which are shown to be associated with neurodegenerative and other clinical features in FRDA (Dantham et al., 2018). These miRNAs have been implicated in autophagy as well as targets of circRNAs in separate studies which warrants further investigations of circRNAs/miRNAs/autophagy axis in FRDA. However, further studies are warranted to find the exact mechanism of autophagy associated circRNAs and their role in FRDA.