small molecules

2026-07-10 | Immune Activation and Glial Dysfunction in Spinocerebellar Ataxias: From Cerebellar Landscape to Disease-Driven Mechanisms and Immunomodulation.

Spinocerebellar ataxias (SCAs) comprise a clinically and genetically heterogeneous group of autosomal dominant neurodegenerative disorders. Despite the recognized role of specialized cerebellar glia in cerebellar development and dysfunction, immune activation and non-immune glial responses remain understudied in SCAs. This narrative review compiles evidence from cellular, animal, and human models on the cerebellar immune landscape and the specific pathways that drive homeostatic failure and neuroinflammatory cascades across SCA subtypes. Microgliosis emerges consistently-and often early- as a generalized feature across the SCA spectrum, preceding neurodegeneration in several subtypes. Concurrently, reactive astrogliosis extends broadly, reflecting widespread macroglial surveillance and metabolic stress regulation throughout histologically preserved gray matter, with specialized homeostatic failure of Bergmann glia in SCA1, SCA2, and SCA7. Peripheral inflammation, manifests as early as the prodromal stage and correlates with the cognitive-affective deficits in SCA2 and associates with the mutation size in SCA3, positioning it as integral to pathogenesis rather than epiphenomenal. Diverse, partially shared signaling pathways converge on multi-lineage glial breakdown and reciprocal neuroimmune crosstalk. These mechanisms involve NF-κB (SCA1,3,17), cGAS-STING (SCA2), TLR/MyD88 (SCA6), and JNK/c-Jun (SCA1,2,7). This review establishes abnormal reciprocal immune/non-immune glia crosstalk as a core pathogenic principle across SCAs, revealing novel therapeutic opportunities. In fact, targeting convergent signaling nodes such as NF-κB, or JNK pathways, holds disease-modifying potential across multiple subtypes. Future research should prioritize standardized comparative studies, longitudinal analyses linking both inflammation and non-immune glial pathology to clinical progression, and clinical trials evaluating targeted immunomodulatory and glial homeostatic-supportive agents.

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2026-05-28 | Aromatic-Turmerone Analogs Activate Chaperone-Mediated Autophagy and Ameliorate Dendritic Shrinkage in Purkinje Cell Models of Spinocerebellar Ataxia.

We recently demonstrated that aromatic (ar)-turmerone analogs ((E)-5-methyl-1-(p-tolyl)hexa-1,4-dien-3-one [A2] and (E)-1-(4-methoxyphenyl)-5-methylhexa-1,4-dien-3-one [A4]) activate chaperone-mediated autophagy (CMA), a pathway in the autophagy-lysosome protein degradation system, in SH-SY5Y cells. Our previous studies revealed that the impairment of CMA and microautophagy (mA), another autophagy-related pathway, and dendritic shrinkage were observed in primary cultured Purkinje cells (PCs) expressing causal proteins of spinocerebellar ataxia (SCA), an autosomal dominant neurodegenerative disease. In the present study, we first investigated the effects of A2 and A4 on lysosomal protein degradation and dendritic morphology in cerebellar primary cultured PCs. Both compounds enhanced dendritic development and activated CMA in cultured PCs. These effects were significantly suppressed by the inhibitors of nuclear factor erythroid 2-related factor 2 and p38. We next examined the effects of A2 and A4 on PCs expressing several types of SCA-causing proteins (SCA model PCs). Both chemicals ameliorated the dendritic shrinkage and restored the decreased CMA/mA activity in several SCA model PCs. These findings suggest that the ar-turmerone analogs A2 and A4 improve the in vitro phenotype of SCA model PCs through CMA activation, highlighting the therapeutic potential of these analogs for various types of SCAs.

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2026-05-10 | Ion Channel Degeneracy Masks Channelopathy in SCA6: Calcium Homeostasis Collapse as a Proteotoxic Stress Mechanism

Spinocerebellar ataxia type 6 (SCA6) is caused by polyglutamine expansion in CACNA1A, encoding the P/Q-type calcium channel (CaPQ). The prevailing channelopathy hypothesis posits that CaPQ loss directly disrupts Purkinje cell firing. Here we test this hypothesis computationally using the Universal Cell v5 biophysically constrained Hodgkin-Huxley framework, simulating 236 elite Purkinje neurons derived from 1.5 million Monte Carlo samples and constrained by Kozareva et al. (2021) cerebellar scRNA-seq data (n = 16,634 cells). Progressive CaPQ reduction — including complete knockout — produced no statistically significant change in firing frequency (51.0 → 51.4 Hz, p ≈ 1.0), demonstrating strong ion channel degeneracy. A sharp phase transition emerged only when CaT was additionally ablated, producing two mechanistically distinct death modes: ca_er_overload and drive_loss. A mechanistic negative control (Ctrl_noCaPQ) confirmed that CaL and CaT loss triggers terminal collapse even with CaPQ fully intact (83.9% survival vs. 83.9% in full disease, p = 1.000), causally excluding CaPQ loss as the primary driver. Rescue simulations across eight mechanisms revealed that HCN augmentation provided the most robust rescue (up to 64%), while PMCA augmentation rescued 12.8–17.1% of drive_loss cells in early phases but collapsed after the Phase 2→3 transition (Fisher's exact OR = ∞, p < 0.0001), defining a therapeutic window closure. Kv3 augmentation was ineffective across all conditions and death modes (0%), ruling out electrical repolarization failure. Independent validation against the Huang et al. (2026) SCA6 mouse time series (GSE264100; n = 40, ages 3–19 months) confirmed the predicted molecular fingerprint: Cacna1h showed progressive divergence from wild-type (WT↑ vs SCA6↓; Spearman ρ = −1.0, p < 0.001), Scn8a declined at 19 months (Log2FC = −0.53, p = 0.016), and PMCA2/Atp2b2 collapsed at late stage, consistent with the computed therapeutic window closure. ER stress markers (BiP/Hspa5 spike-then-collapse; CHOP/Ddit3 ↑ → p_adj = 4.6 × 10⁻¹²) confirmed proteotoxic rather than electrophysiological pathology. We conclude that SCA6 is not a primary channelopathy: ion channel degeneracy masks CaPQ loss at the firing level, while downstream CaT erosion and ER calcium overload drive neurodegeneration independently of P/Q-type channel function.

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2026-02-22 | Long-term efficacy and disease-specific responsiveness to protirelin in patients with spinocerebellar degeneration: A retrospective study.

The thyrotropin-releasing hormone (TRH) analog protirelin has short-term benefits for cerebellar ataxia (CA), but its long-term efficacy and the subtype-specific responsiveness of spinocerebellar degeneration (SCD) patients remain unclear. We retrospectively reviewed the records of 92 SCD patients (273 courses) treated with protirelin between July 2011 and October 2025, including patients with idiopathic CA (IDCA), multiple system atrophy with predominant CA (MSA-C) or parkinsonism (MSA-P), and genetic subtypes including spinocerebellar ataxia (SCA) type 6, SCA31 and dentatorubral-pallidoluysian atrophy (DRPLA). Responders were defined as showing ≥1-point improvement on the Scale for the Assessment and Rating of Ataxia (SARA). Protirelin was effective in 64.1% of subjects, with significant improvement overall (p < 0.001) and significant SARA gains in MSA-C (p = 0.047), IDCA (p = 0.02), and SCA31 (p = 0.01). Change in SARA score (ΔSARA) correlated negatively with age and positively with total protirelin dose in IDCA, and negatively with age and disease duration and positively with baseline SARA score in SCA31. Several IDCA and DRPLA patients maintained clinical benefit for more than 10 years. All MSA-P discontinued protirelin within 2 years and all MSA-C within 5 years; some SCA6, and SCA31 patients continued for ≥5 years. Adverse effects were infrequent (2/92, 2.2%). Protirelin is efficacious in SCD patients and well-tolerated, particularly in slow-progressing phenotypes (IDCA and SCA31); its benefit in rapidly progressing ataxias (MSA-C) may be confined to early disease stages. Prospective studies with standardized dosing and long-term follow-up are warranted to establish evidence-based protocols for TRH-related therapy for CA.

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2026-02-19 | The Hsp40 cochaperone DNAJC7 regulates polyglutamine aggregation and exhibits context-dependent effects on polyglycine aggregation.

Protein-encoding nucleotide repeat expansion diseases, including polyglutamine (polyQ) and polyglycine (polyG) diseases, are characterized by the accumulation of aggregation-prone proteins. In the polyQ diseases, including Huntington's disease and several spinocerebellar ataxias, substantial prior evidence supports a pathogenic role for mutant polyQ-expanded protein misfolding and aggregation, with molecular chaperones showing promise in suppressing disease phenotypes in cellular and animal models. The goal of this study is to establish a scalable cell-based model to systematically evaluate genetic modifiers of protein aggregation in both polyQ and polyG diseases. We developed FRET-based reporter systems that model polyQ and polyG aggregation in human cells and used them to perform high-throughput CRISPR interference screens targeting all known molecular chaperones. In the polyQ model, the screen identified multiple Hsp70 chaperones and Hsp40 cochaperones previously implicated in polyQ aggregation and additionally revealed the Hsp40 cochaperone DNAJC7 as a potent and previously unrecognized suppressor of polyQ aggregation. In contrast, in a FRET-based polyG aggregation model of neuronal intranuclear inclusion disease, CRISPR interference screening showed minimal overlap of chaperone modifiers of the polyQ screen. Direct knockdown of DNAJC7 also did not affect polyG aggregation, yet overexpressed DNAJC7 colocalized with both polyQ and polyG aggregates in cells and reduced their aggregation. In addition to establishing new inducible, scalable cellular models for polyQ and polyG aggregation, this work expands the role of DNAJC7 in regulating the folding of disease-associated proteins.

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proteins

2025-09-22 | Stimulation of Purkinje cell firing reverses early onset spatial navigation deficits in a spinocerebellar ataxia type 6 mouse model.

Spinocerebellar ataxia type 6 (SCA6) is a hereditary neurodegenerative disease that manifests in a late onset and progressive impairment of motor coordination, balance and speech as well as cerebellar and brainstem atrophy. It is caused by a polyglutamine expansion in the CACNA1A gene which bicistronically encodes the α1A-subunit of the P/Q-type voltage-gated calcium channel and the transcription factor α1ACT. The lack of treatments for SCA6 patients emphasizes the necessity to investigate the underlying pathomechanisms and its impact on cognition. In this study we found that SCA6 mice demonstrate spatial navigation deficits which precede their motor deficiencies. This resulted in a concomitant Purkinje cell (PC) dysfunction, exhibited by a disruption in their PC spontaneous simple spike firing rates and regularity of firing. PC dysfunction was further confirmed by elevated numbers of axonal swellings found in the PC proximal axons throughout the cerebellum. More importantly, we were able to partially rescue irregular PC firing and spatial navigation deficits using a stimulatory Gq-protein coupled designer receptor exclusively activated by a designer drug (Gq-DREADD), further indicating that PC dysfunction contributes to SCA6 cognitive abnormalities in spatial navigation.

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2025-08-20 | The Hsp40 co-chaperone DNAJC7 modifies polyglutamine but not polyglycine aggregation.

Polyglutamine (polyQ) diseases, including Huntington's disease and several spinocerebellar ataxias, are caused by abnormally expanded CAG nucleotide repeats, which encode aggregation-prone polyQ tracts. Substantial prior evidence supports a pathogenic role for polyQ protein misfolding and aggregation, with molecular chaperones showing promise in suppressing disease phenotypes in cellular and animal models. In this study, we developed a FRET-based reporter system that models polyQ aggregation in human cells and used it to perform a high-throughput CRISPR interference screen targeting all known molecular chaperones. This screen identified as a strong suppressor of polyQ aggregation the Hsp40 co-chaperone DNAJC7, which has previously been shown to modify aggregation of other disease proteins (tau and TDP-43) and has mutations causative for amyotrophic lateral sclerosis. We validated this phenotype and further established a physical interaction between DNAJC7 and polyQ-expanded protein. In contrast, DNAJC7 did not modify aggregation of polyglycine (polyG) in a FRET-based model of neuronal intranuclear inclusion disease. In addition to establishing new inducible, scalable cellular models for polyQ and polyG aggregation, this work expands the role of DNAJC7 in regulating folding of disease-associated proteins.

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2025-02-26 | Reduced cerebellar rhythm by climbing fiber denervation is linked to motor rhythm deficits in mice and ataxia severity in patients

Cerebellar ataxia results from various genetic and nongenetic disorders and is characterized by involuntary movements that impair precision and motor rhythm. Here, we report that climbing fiber (CF) denervation is a common pathophysiology underlying motor rhythm loss in cerebellar ataxia. By examining cerebellar pathology in patients with spinocerebellar ataxia (SCA) types 1, 2, and 6 and multiple system atrophy, we identified CF degeneration with synaptic loss as a shared pathophysiology. Optogenetic silencing of CF synaptic activity in mice induced ataxia-like motor dysfunctions and loss of motor precision. In addition, CF silencing resulted in cerebellar and motor rhythm loss, another core feature of ataxia. This rhythm loss was predominantly CF dependent and resistant to Purkinje cell-specific lesioning by diphtheria toxin. Correspondingly, two patients with inferior olive pathology, the brain site that provides CFs to Purkinje cells, presented with ataxia and cerebellar rhythm loss. Patients with genetic or nongenetic cerebellar ataxia exhibited cerebellar rhythm loss that correlated with the Scale for the Assessment and Rating of Ataxia. Chemogenetic stimulation of CFs improved cerebellar and motor rhythms as well as motor performance in the SCA type 1 mouse model of ataxia. These results suggest that CF-dependent cerebellar rhythm loss occurs across different types of cerebellar ataxia, contributing to motor imprecision and motor rhythm loss, two defining features of ataxia.

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2024-12-27 | Genetic modeling of degenerative diseases and mechanisms of neuronal regeneration in the zebrafish cerebellum.

The cerebellum is a highly conserved brain compartment of vertebrates. Genetic diseases of the human cerebellum often lead to degeneration of the principal neuron, the Purkinje cell, resulting in locomotive deficits and socio-emotional impairments. Due to its relatively simple but highly conserved neuroanatomy and circuitry, these human diseases can be modeled well in vertebrates amenable for genetic manipulation. In the recent years, cerebellar research in zebrafish has contributed to understanding cerebellum development and function, since zebrafish larvae are not only molecularly tractable, but also accessible for high resolution in vivo imaging due to the transparency of the larvae and the ease of access to the zebrafish cerebellar cortex for microscopy approaches. Therefore, zebrafish is increasingly used for genetic modeling of human cerebellar neurodegenerative diseases and in particular of different types of Spinocerebellar Ataxias (SCAs). These models are well suited to address the underlying pathogenic mechanisms by means of in vivo cell biological studies. Furthermore, accompanying circuitry characterizations, physiological studies and behavioral analysis allow for unraveling molecular, structural and functional relationships. Moreover, unlike in mammals, zebrafish possess an astonishing ability to regenerate neuronal populations and their functional circuitry in the central nervous system including the cerebellum. Understanding the cellular and molecular processes of these regenerative processes could well serve to counteract acute and chronic loss of neurons in humans. Based on the high evolutionary conservation of the cerebellum these regeneration studies in zebrafish promise to open therapeutic avenues for counteracting cerebellar neuronal degeneration. The current review aims to provide an overview over currently existing genetic models of human cerebellar neurodegenerative diseases in zebrafish as well as neuroregeneration studies using the zebrafish cerebellum. Due to this solid foundation in cerebellar disease modeling and neuronal regeneration analysis, the zebrafish promises to become a popular model organism for both unraveling pathogenic mechanisms of human cerebellar diseases and providing entry points for therapeutic neuronal regeneration approaches.

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2023-09-13 | Reduced cerebellar Gq-protein signaling elicits early onset spatial navigation deficits in a SCA6 mouse model

Abstract Spinocerebellar ataxia type 6 (SCA6) is a hereditary neurodegenerative disease that manifests in a late onset and progressive impairment of motor coordination, balance and speech as well as cerebellar and brainstem atrophy. It is caused by a polyglutamine expansion in the CACNA1A gene which bicistronically encodes the α1A-subunit of the P/Q-type voltage-gated calcium channel and the transcription factor α1ACT. To date, no effective treatment exists and the exact pathobiology is controversially discussed; especially the impact on cognition is poorly understood. Here, we demonstrate that SCA6 84Q mice exhibit cognitive deficits in their spatial navigation abilities. Surprisingly, spatial memory impairments develop prior to motor impairments at 5 months of age. By expressing and stimulating a Gq-protein coupled designer receptor exclusively activated by a designer drug (Gq-DREADD) in the cerebellum, we were able to counteract these spatial navigation deficits indicating that a reduced Gq-protein signaling is part of the SCA6 phenotype. Electrophysiological recordings in anaesthetized mice further revealed that Purkinje cells (PCs) of SCA6 84Q mice exhibit a disrupted spontaneous simple spike activity that precedes the development of both cognitive and motor deficits. Concurrently, PC dysfunction was further confirmed by elevated numbers of torpedoes found in the proximal axon of PCs throughout the cerebellum. Overall, our study raises awareness to survey cognitive abnormalities more carefully during clinical examination to detect the disease earlier and potentially optimize the individual treatment by enhancing PC signaling. Significance statement SCA6 is a hereditary neurological disease that is mainly characterized by the late-onset development of progressive motor deficits. Here we show, using a SCA6 mouse model, that cognitive impairments in spatial navigation are also a non-negligible feature of the disease which manifests earlier than the motor deficits. Moreover, we demonstrate that these spatial navigation deficits are caused by a reduced Gq-protein signaling in the cerebellum. Electrophysiological and histological analysis further confirmed dysfunctional PC signaling even before the onset of first symptoms. Since no effective treatment is available for SCA6 patients, early onset stimulation of PC signaling may be a new therapeutic approach.

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gene therapies

2026-07-09 | Gene therapy for spinocerebellar ataxias.

Spinocerebellar ataxias (SCAs), rare neurodegenerative disorders characterized by progressive cerebellar degeneration, cause impaired balance and motor dysfunction. Although most cases are inherited, sporadic forms also occur, and effective disease-modifying therapies remain unavailable despite advances in understanding their genetic and molecular mechanisms. This unmet need is particularly significant because many SCAs are monogenic disorders caused by well-characterized mutations, making them promising candidates for gene- and RNA-based therapies. Recent advances in antisense oligonucleotides, RNA interference, vector engineering, and genome editing have increasingly enabled the alignment of therapeutic strategies with specific mutational architectures. Therefore, this review aims to examine how genetic subclassification informs platform selection, summarize recent advances in gene- and RNA-based therapeutics, and outline key translational barriers to clinical implementation in SCAs.

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2026-04-24 | Developmental roots of cerebellar degeneration in spinocerebellar ataxia.

Late-onset neurodegenerative diseases have long been conceptualized as disorders arising from cumulative cellular stress and age-related decline, with pathology emerging at the time of symptom onset. However, emerging evidence challenges this view, suggesting that developmental perturbations may establish early vulnerabilities that predispose specific neuronal populations to degeneration later in life. In the cerebellum, mutations causing spinocerebellar ataxias (SCAs) such as SCA1 and SCA6 affect genes involved in normal circuit formation, resulting in subtle early abnormalities in Purkinje cell activity and connectivity. These alterations seem to be initially buffered by compensatory mechanisms, and the eventual breakdown of homeostatic resilience during midlife may thus be the trigger for disease onset and progression. This developmental perspective reframes late-onset neurodegeneration as a lifelong process shaped by the interplay between early developmental wiring, adaptive compensation, and age-dependent vulnerability. Understanding these early developmental alterations provides critical insight into disease mechanisms and opens new avenues for pre-symptomatic intervention and prevention.

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2026-02-12 | Patient-reported Vision Quality-of-life in Parkinsonian Syndromes and Ataxias and Association with Clinical Oculomotor Findings.

Oculomotor dysfunction is common in parkinsonian syndromes and ataxias, but its impact on patient-reported vision-related quality of life (VQoL) remains insufficiently understood. To characterize VQoL across parkinsonian syndromes and ataxias and assess the functional significance of specific oculomotor abnormalities in spinocerebellar ataxias. Participants were recruited at Massachusetts General Hospital ( n =231): 104 with Parkinson's disease (PD), 10 with progressive supranuclear palsy (PSP), 56 with genetically defined ataxias (SCA2, SCA3, SCA6, SCA27B, CANVAS), and 61 healthy controls. VQoL was assessed using a 13-item subset of the Visual Activities Questionnaire targeting depth perception, visual acuity/spatial vision, and visual processing speed. Clinical severity was assessed with the Brief Ataxia Rating Scale and Modified International Cooperative Ataxia Rating Scale, and subjective symptoms with PROM-Ataxia. Group comparisons, correlations, and regression analyses were performed. All disease groups reported significantly worse VQoL than controls, with the largest deficits in visual processing speed. PSP showed the greatest impairment across all domains, while PD was less affected. Individuals with SCA3 and SCA6 had significantly lower VQoL across all subcategories. In ataxias, VQoL correlated moderately with PROM-Ataxia and weakly with clinical oculomotor scores. Gaze-evoked nystagmus was the only oculomotor sign independently associated with reduced VQoL. Parkinsonian syndromes and ataxias are associated with substantial VQoL impairment, particularly in visual processing speed. Gaze-evoked nystagmus is a key predictor of reduced VQoL in ataxias, highlighting the functional relevance of fixation instability. Patient-reported outcomes and oculomotor assessments are essential for capturing visual disability in clinical care and trials.

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2025-11-27 | Psychomotor and non-motor correlates of cognition in spinocerebellar ataxias Types 1, 2, 3, and 6.

There is growing evidence of cognitive deficits in spinocerebellar ataxias, with the Cerebellar Cognitive Affective Syndrome Scale (CCAS-S) an increasingly common measure of this dysfunction. There remain ongoing questions as to how Cerebellar Cognitive Affective Syndrome Scale performance relates to day-to-day cognitive function, non-motor and motor features of spinocerebellar ataxias and demographic factors. Via an online study, we evaluated Cerebellar Cognitive Affective Syndrome Scale performance amongst individuals with spinocerebellar ataxia Type 1 (n = 14), Type 2 (n = 16), Type 3 (n = 18), and Type 6 (n = 26) relative to demographically-matched control groups. Furthermore, amongst individuals with spinocerebellar ataxia, we examined associations between performance and (i) age and education, (ii) ataxia motor severity, (iii) psychomotor function measured by computerized finger tapping and reaction time tasks and (iv) self-rated cognition, depression, emotional regulation, psychosocial function and fatigue. Cerebellar Cognitive Affective Syndrome Scale performance was significantly reduced in spinocerebellar ataxia Types 2, 3, and 6 compared to controls, although substantial inter-individual variability in performance was observed in the spinocerebellar ataxia cohort (43.2%/24.3%/21.6%/10.8% met criteria for Definite, Probable, Possible, and No CCAS). Performance in individuals with spinocerebellar ataxias correlated significantly with self-reported ataxia motor severity, fine motor speed, psychomotor trial-by-trial variability, and one of two measures of day-to-day cognitive function. Significant correlations were not observed against age, education, age at disease onset, disease duration, psychomotor reaction time, depression, emotional regulation, psychosocial function, or fatigue. We present evidence that motor function and psychomotor variability are more important correlates of inter-individual variability in cognitive performance amongst people with spinocerebellar ataxia Types 1, 2, 3 and 6, compared to demographic factors, fatigue, or emotional function. Importantly, formalized cognitive testing using the Cerebellar Cognitive Affective Syndrome Scale correlates with self-reported cognitive functioning. This study highlights cognitive dysfunction as a functionally impactful feature of certain spinocerebellar ataxias, and motivates further investigation into the disease- and individual-specific profiles of cognitive impairment in this population.

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2025-11-22 | Development of a Gene Therapy with Lentiviral Vectors for Spinocerebellar Ataxias.

Among viral vectors, lentiviral vectors allow an efficient delivery of nucleic acid to the target cells due to its ability of gene integration into host genome and broad tropism. In this sense, this tool demonstrated to be very promising in genetic disorders, such as polyglutamine spinocerebellar ataxias. Therefore, we describe a protocol that explains in detail the production, purification, and injection of lentiviral vectors in a spinocerebellar ataxia mouse model.

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oligonucleotides

2026-01-19 | An acyclic nucleic acid-modified siRNA targeting CAG expansions for polyglutamine disease treatment.

Polyglutamine (polyQ) diseases are inherited neurological disorders caused by an expansion of the cytosine-adenine-guanine (CAG) repeat in the causative genes. These include Huntington's disease, spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxias (SCAs). Clinical trials have been conducted using nucleic acid therapeutics to silence the causative gene for these diseases, but none have been approved for use. Furthermore, while oligonucleotides targeting the CAG repeats are an attractive therapeutic option, concomitant silencing of the wild-type allele with normal CAG repeats can result in neuronal dysfunction. In this study, we developed an acyclic serinol nucleic acid (SNA)-modified small interfering RNA (siRNA) targeting CAG repeats. We also evaluated the safety and efficacy of the siRNA in different mouse models of polyQ diseases. Intracerebroventricularly administered siRNA was widely distributed throughout the central nervous system, where it selectively silenced the alleles encoding polyQ proteins without affecting their wild-type counterparts. Consequently, the intranuclear aggregation of polyQ proteins was reduced in mouse models of SBMA and SCA type 3. The siRNA attenuated neuromuscular degeneration and improved the lifespan and motor function of the SBMA mice. These findings suggest that SNA-modified siRNAs targeting CAG repeats represent a promising approach for treating polyQ diseases.

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2024-06-19 | Spinocerebellar ataxias: from pathogenesis to recent therapeutic advances.

Spinocerebellar ataxia is a phenotypically and genetically heterogeneous group of autosomal dominant-inherited degenerative disorders. The gene mutation spectrum includes dynamic expansions, point mutations, duplications, insertions, and deletions of varying lengths. Dynamic expansion is the most common form of mutation. Mutations often result in indistinguishable clinical phenotypes, thus requiring validation using multiple genetic testing techniques. Depending on the type of mutation, the pathogenesis may involve proteotoxicity, RNA toxicity, or protein loss-of-function. All of which may disrupt a range of cellular processes, such as impaired protein quality control pathways, ion channel dysfunction, mitochondrial dysfunction, transcriptional dysregulation, DNA damage, loss of nuclear integrity, and ultimately, impairment of neuronal function and integrity which causes diseases. Many disease-modifying therapies, such as gene editing technology, RNA interference, antisense oligonucleotides, stem cell technology, and pharmacological therapies are currently under clinical trials. However, the development of curative approaches for genetic diseases remains a global challenge, beset by technical, ethical, and other challenges. Therefore, the study of the pathogenesis of spinocerebellar ataxia is of great importance for the sustained development of disease-modifying molecular therapies.

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2024-02-05 | Widespread alternative splicing dysregulation occurs presymptomatically in CAG expansion spinocerebellar ataxias.

The spinocerebellar ataxias (SCAs) are a group of dominantly inherited neurodegenerative diseases, several of which are caused by CAG expansion mutations (SCAs 1, 2, 3, 6, 7 and 12) and more broadly belong to the large family of over 40 microsatellite expansion diseases. While dysregulation of alternative splicing is a well defined driver of disease pathogenesis across several microsatellite diseases, the contribution of alternative splicing in CAG expansion SCAs is poorly understood. Furthermore, despite extensive studies on differential gene expression, there remains a gap in our understanding of presymptomatic transcriptomic drivers of disease. We sought to address these knowledge gaps through a comprehensive study of 29 publicly available RNA-sequencing datasets. We identified that dysregulation of alternative splicing is widespread across CAG expansion mouse models of SCAs 1, 3 and 7. These changes were detected presymptomatically, persisted throughout disease progression, were repeat length-dependent, and were present in brain regions implicated in SCA pathogenesis including the cerebellum, pons and medulla. Across disease progression, changes in alternative splicing occurred in genes that function in pathways and processes known to be impaired in SCAs, such as ion channels, synaptic signalling, transcriptional regulation and the cytoskeleton. We validated several key alternative splicing events with known functional consequences, including Trpc3 exon 9 and Kcnma1 exon 23b, in the Atxn1154Q/2Q mouse model. Finally, we demonstrated that alternative splicing dysregulation is responsive to therapeutic intervention in CAG expansion SCAs with Atxn1 targeting antisense oligonucleotide rescuing key splicing events. Taken together, these data demonstrate that widespread presymptomatic dysregulation of alternative splicing in CAG expansion SCAs may contribute to disease onset, early neuronal dysfunction and may represent novel biomarkers across this devastating group of neurodegenerative disorders.

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2023-11-22 | From the disruption of RNA metabolism to the targeting of RNA-binding proteins: The case of polyglutamine spinocerebellar ataxias.

Polyglutamine spinocerebellar ataxias (PolyQ SCAs) represent a group of monogenetic diseases in which the expanded polyglutamine repeats give rise to a mutated protein. The abnormally expanded polyglutamine protein produces aggregates and toxic species, causing neuronal dysfunction and neuronal death. The main symptoms of these disorders include progressive ataxia, motor dysfunction, oculomotor impairment, and swallowing problems. Nowadays, the current treatments are restricted to symptomatic alleviation, and no existing therapeutic strategies can reduce or stop the disease progression. Even though the origin of these disorders has been associated with polyglutamine-induced toxicity, RNA toxicity has recently gained relevance in polyQ SCAs molecular pathogenesis. Therefore, the research's focus on RNA metabolism has been increasing, especially on RNA-binding proteins (RBPs). The present review summarizes RNA metabolism, exposing the different processes and the main RBPs involved. We also explore the mechanisms by which RBPs are dysregulated in PolyQ SCAs. Finally, possible therapies targeting the RNA metabolism are presented as strategies to reverse neuropathological anomalies and mitigate physical symptoms.

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2023-04-14 | Gene Suppression Therapies in Hereditary Cerebellar Ataxias: A Systematic Review of Animal Studies.

Hereditary cerebellar ataxias (HCAs) are a heterogenous group of neurodegenerative disorders associated with severe disability. Treatment options are limited and overall restricted to symptomatic approaches, leading to poor prognoses. In recent years, there has been extensive research on gene suppression therapies (GSTs) as a new hope for disease-modifying strategies. In this article, we aim to perform a review of in vivo studies investigating the efficacy and safety profile of GSTs in HCAs. A structured PubMed® search on GSTs in HCAs from January 1993 up to October 2020 was performed. Inclusion and exclusion criteria were defined, and the selection process was conducted accordingly. The screening process was independently carried out by two authors and was initially based on title and abstract, followed by full-text reading. The risk-of-bias assessment was performed with SYRCLE's tool. A data extraction sheet was created to collect relevant information from each selected article. The initial search yielded 262 papers, of which 239 were excluded. An additional article was obtained following reference scrutiny, resulting in a total of 24 articles for final analysis. Most studies were not clear on the tools used to assess bias. In SCA1, SCA2, MJD/SCA3 and SCA7, RNA interference (iRNA) and antisense oligonucleotide (ASO) therapies proved to be well tolerated and effective in suppressing mutant proteins, improving neuropathological features and the motor phenotype. In SCA6, the phenotype was improved, but no investigation of adverse effects was performed. In FRDA, only the suppression efficacy of the electroporation of the clustered regularly interspaced short palindromic repeats associated with Cas9 enzyme system (CRISPR-Cas9) system was tested and confirmed. The literature reviewed suggests that GSTs are well tolerated and effective in suppressing the targeted proteins, improving neuropathological features and the motor phenotype in vivo. Nonetheless, there is no guarantee that these results are free of bias. Moreover, further investigation is still needed to clarify the GST effect on HCAs such as FRDA, SCA6 and SCA2.

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other

2026-07-11 | Safety and preliminary efficacy of autologous bone marrow-derived mesenchymal stem cell transplantation in hereditary cerebellar ataxia: phase I/IIa clinical trial.

Hereditary cerebellar ataxias (HCA) encompass a spectrum of pathological conditions affecting the cerebellum. Currently, there is growing interest in the potential role of mesenchymal stem cells (MSCs) as an investigational therapeutic approach for this condition. Hence, the objective of this single-center, open-label, phase I/IIa clinical trial was to assess the safety and exploratory clinical and biomarker changes following a single intrathecal injection of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in HCA. Ten confirmed patients with HCA entered the study and underwent a single dose of (1 × 106 cells/kg BW) intrathecal transplantation of BM-MSCs at passage 3. During the follow-up, patients were evaluated four times (one month before the intervention (-1), months 1, 3, and 6). Assessments included safety evaluation, Scale for the Assessment and Rating of Ataxia (SARA), GAD 65-antibody, and specific cytokines in the patient's serum and cerebrospinal fluid (CSF) samples. No severe adverse effects were observed following the cell transplantation procedure. A decreasing trend in SARA score was observed, with a statistically significant difference at month 6 compared with baseline. Except for one patient, GAD-65 antibody levels remained within the normal range in all patients. In one patient with markedly elevated baseline GAD-65 titers, serum and CSF GAD-65 levels decreased from 814 IU/mL and 781 IU/mL, respectively, to values within the normal range after 3 months. Significant changes were observed in selected inflammatory biomarkers, including decreased serum IL-6 at month 3, decreased CSF TNF-alpha at months 1 and 3, and increased serum IL-10 during follow-up. CSF IL-6 did not show a significant decrease. The findings support the short-term safety and tolerability of a single intrathecal dose of autologous BM-MSCs in this small HCA cohort. The study provides preliminary signals of possible clinical and biomarker changes; however, efficacy cannot be established due to the uncontrolled design, small sample size, disease heterogeneity, and short follow-up. Larger randomized controlled trials are required to validate these exploratory findings. This clinical trial was registered with the Iranian Registry of Clinical Trials (ID: IRCT20160809029275N3).

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2025-03-25 | <i>In vitro</i> study: generation of a non-invasive patient-derived neurodegenerative model for spinocerebellar ataxia 6

Background: Spinocerebellar ataxia (SCA) is a rare neurodegenerative disorder defined by genetic mutations that cause gait disturbances and impaired motor coordination. Among its subtypes, SCA6 arises from mutations in the CACNA1A gene that disrupt calcium signaling and lead to neuronal cell death. Despite extensive research, no effective treatments are available.Methods: In this study, we established a non-invasive, patient-derived induced pluripotent stem cell (iPSC) model to investigate the pathological mechanisms of SCA6. Urinary cells collected from an SCA6 patient were successfully reprogrammed into iPSCs, as confirmed by alkaline phosphatase staining and the expression of key pluripotency markers.Results: These iPSCs were subsequently differentiated into cerebellar organoids that progressively exhibited characteristic cerebellar neuron markers. Phenotypic analysis revealed significant abnormalities in SCA6-derived cerebellar neurons, including reduced organoid size, impaired neurite formation, and decreased expression of KIRREL, a marker of Purkinje cells.Conclusion: These findings indicate that our iPSC-derived cerebellar organoid model effectively recapitulates key pathological features of SCA6, providing a valuable platform for elucidating the cellular mechanisms underlying this disorder and for developing targeted therapeutic approaches.

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2022-04-05 | Human Induced Pluripotent Stem Cell-Based Modelling of Spinocerebellar Ataxias.

Dominant spinocerebellar ataxias (SCAs) constitute a large group of phenotypically and genetically heterogeneous disorders that mainly present with dysfunction of the cerebellum as their main hallmark. Although animal and cell models have been highly instrumental for our current insight into the underlying disease mechanisms of these neurodegenerative disorders, they do not offer the full human genetic and physiological context. The advent of human induced pluripotent stem cells (hiPSCs) and protocols to differentiate these into essentially every cell type allows us to closely model SCAs in a human context. In this review, we systematically summarize recent findings from studies using hiPSC-based modelling of SCAs, and discuss what knowledge has been gained from these studies. We conclude that hiPSC-based models are a powerful tool for modelling SCAs as they contributed to new mechanistic insights and have the potential to serve the development of genetic therapies. However, the use of standardized methods and multiple clones of isogenic lines are essential to increase validity and reproducibility of the insights gained.

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2016-08-15 | Transplantation of Embryonic Cerebellar Grafts Improves Gait Parameters in Ataxic Lurcher Mice.

Hereditary cerebellar ataxias are severe diseases for which therapy is currently not sufficiently effective. One of the possible therapeutic approaches could be neurotransplantation. Lurcher mutant mice are a natural model of olivocerebellar degeneration representing a tool to investigate its pathogenesis as well as experimental therapies for hereditary cerebellar ataxias. The effect of intracerebellar transplantation of embryonic cerebellar solid tissue or cell suspension on motor performance in adult Lurcher mutant and healthy wild-type mice was studied. Brain-derived neurotrophic factor level was measured in the graft and adult cerebellar tissue. Gait analysis and rotarod, horizontal wire, and wooden beam tests were carried out 2 or 6 months after the transplantation. Higher level of the brain-derived neurotrophic factor was found in the Lurcher cerebellum than in the embryonic and adult wild-type tissue. A mild improvement of gait parameters was found in graft-treated Lurcher mice. The effect was more marked in cell suspension grafts than in solid transplants and after the longer period than after the short one. Lurcher mice treated with cell suspension and examined 6 months later had a longer hind paw stride (4.11 vs. 3.73 mm, P < 0.05) and higher swing speed for both forepaws (52.46 vs. 32.79 cm/s, P < 0.01) and hind paws (63.46 vs. 43.67 cm/s, P < 0.001) than controls. On the other hand, classical motor tests were not capable of detecting clearly the change in the motor performance. No strong long-lasting negative effect of the transplantation was seen in wild-type mice, suggesting that the treatment has no harmful impact on the healthy cerebellum.

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2015-12-01 | Mesenchymal stem cells as a potential therapeutic tool for spinocerebellar ataxia.

Spinocerebellar ataxia (SCA) is a devastating progressive neurodegenerative disorder, for which no effective treatments have been developed. However, some studies have shown that an intracerebellar or intrathecal injection of mesenchymal stem cells (MSCs) was partially effective in some genetic mouse models of cerebellar ataxia such as SCA1 and Lurcher mutant. MSCs likely exert their therapeutic efficacy by secreting innate factors to induce neuronal growth and synaptic connection and reduce apoptosis. In this review, we introduce the therapeutic influence of MSCs on each mouse model for cerebellar ataxia and the possible mechanisms underlying the action of MSCs. We also introduce studies on the safety and effectiveness of umbilical cord MSCs for patients with SCA.

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