RARE DISEASE
Spinocerebellar ataxia type 1
Spinocerebellar ataxia type 1
Spinocerebellar ataxia type 1
Synonyms: SCA1
Synonyms: SCA1
Synonyms: SCA1
Drug discovery
2
drugs
With orphan designations
Overview
Spinocerebellar Ataxia Type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansions (≥40 repeats) in the ATXN1 gene. It manifests as progressive cerebellar ataxia, dysarthria, ophthalmoplegia, and bulbar dysfunction, with onset typically in early adulthood (4th decade). Pathologically, mutant ataxin-1 protein aggregation causes Purkinje cell loss and brainstem degeneration. Survival averages 10-20 years post-symptom onset, with death often due to respiratory complications [1][4][6].
Burden
73.7% of patients require assistive devices within 10 years; 81% of SCA1 patients report ≥5 falls/year [9][14]
SF-36 physical component scores 30-40% below population norms; 86% experience fear-of-falls impacting daily life [9][14]
Economic burden: 60% require caregiver support, with 40% unable to work within 15 years of onset [9][16]
Therapies
Genetic: Antisense oligonucleotides (ASOs) targeting ATXN1 mRNA and CRISPR-based approaches in preclinical stages [3][8]
Pharmacological: Riluzole (glutamate modulation), chlorzoxazone/baclofen (ion channel modulation), and phosphodiesterase inhibitors targeting downstream pathways [3][13]
Supportive: Multidisciplinary care (speech/physiotherapy), fall prevention, and aspiration management [9][16]
Categories: rare genetic diseases, rare neurological diseases, rare ophthalmic disorders
Research Papers
329 drug discovery papers about Spinocerebellar ataxia type 1, with 6 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
329 drug discovery papers about Spinocerebellar ataxia type 1, with 6 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-03-12 | Retrotransposition Events Shape the Evolution of the Ataxin-3 Gene Family in Primates.
Evolutionary studies of disease-associated genes provide crucial insights into pathological mechanisms and potential therapeutic targets. Polyglutamine spinocerebellar ataxias (SCAs) are human neurodegenerative diseases caused by toxic expanded CAG repeats. Studies on SCA1 have shown that a paralog of the causing-gene can partially rescue protein function and alleviate the neuropathology. The most common SCA, Machado-Joseph disease (MJD/SCA3), caused by mutated ataxin-3 gene (ATXN3), has no treatment currently available. Its paralog ataxin-3 like (ATXN3L) remains largely unexplored. Here, we identify three new retrotransposition events of ATXN3: ATXN3L0 in Euarchontoglires, ATXN3L2 in Simiformes, and ATXN3L3 in Cercopithecidae, in addition to ATXN3L (herein called ATXN3L1) originated in Haplorrhini. ATXN3 and ATXN3L1 are both under purifying selection throughout primate evolution, maintaining about 70% of amino acid identity. Also, the high conservation of ATXN3L1 Josephin domain hints at functional redundancy with the parental disease-associated ATXN3. ATXN3L2 presents a remarkable nucleotide similarity to ATXN3 (79%) in an interrupted reading frame, which may produce a regulatory RNA. Conversely, ATXN3L0 is likely a non-functional retrocopy and ATXN3L3 is absent in humans with no relevance for the disease. The comparison of (CAG)n interruption patterns of the different paralogs in several primates elucidates the process leading to the currently observed pure long tracts in human ATXN3, responsible for disease when expanded. This study intends to pioneer the identification of new paralogs of SCA-associated genes and the use of phylogenetic analyses to explore their potential role for targeted therapies.
2026-02-12 | Long-term efficacy and disease-specific responsiveness to protirelin in patients with spinocerebellar degeneration: A retrospective study
INTRODUCTION: 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. METHODS: 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). RESULTS: 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%). CONCLUSION: 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.
2025-10-02 | Spinocerebellar Ataxia Type 1 (SCA1) Cell Models Display Widespread Mitochondrial and Extra-Nuclear Alterations.
Ataxin-1 (ATXN1) is a nuclear-cytoplasmic shuttling protein, which, when expanded in its polyglutamine coding stretch, causes the progressive neurodegenerative disease Spinocerebellar Ataxia Type 1 (SCA1). While the role of nuclear ATXN1 as a repressor of transcription and regulator of splicing is well studied, its potential cytoplasmic role is more ambiguous. We previously demonstrated mitochondrial dysfunction- including altered respiration and enhanced oxidative stress- is associated with early SCA1 pathogenesis in mice. Moreover, intervention with the electron transport chain substrate succinic acid ameliorated Purkinje cell atrophy and cerebellar behavioral deficits. We now hypothesize that mitochondrial dysfunction in SCA1 may be at least partially due to cytoplasmic interactions between ATXN1 and mitochondria, rather than a result of mutant ATXN1's altered nuclear function. In order to characterize the extent of mitochondrial dysfunction due to mutant ATXN1, we turned to cerebellar-derived Daoy cells which endogenously express human wild type ATXN1. Our SCA1 Daoy model stably over-express phosphorylation-prone, nuclear-aggregating ATXN1[82]. Despite the short lifespan (~ 33 h), Daoy SCA1 cells reveal gross morphological, compositional, and physiological deficits. Conversely, expression in Daoy of a phosphorylation-resistant, cytoplasm-degradable, non-aggregating ATXN1 (ATXN1[82Q-A776]) selectively resulted in intermediate physiological phenotypes and altered mitochondrial protein composition. Finally, our meta-analysis of previously published data supports direct interactions between mutant polyglutamine-expanded ATXN1 and mitochondrial proteins involved in apoptosis, oxidative phosphorylation, composition, and transcription. Our data therefore suggest that irrespective of a disease context and ATXN1[82Q] nuclear aggregation, mitochondrial deficits occur. Overall, the results of this study show mutant ATXN1 can affect metabolic processes outside of its deleterious effect on transcription and splicing, and highlights its multifaceted and multicompartmental function.
2025-03-17 | Chemical targeting of the ATXN1 aa99-163 interaction site suppresses polyQ-expanded protein dimerization
ABSTRACT Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a polyglutamine (polyQ) tract in the ATXN1 protein. This expansion is thought to be responsible for the gradual aggregation of the mutant protein, which is associated with increased cytotoxicity and neuronal cell death. Apart from the polyQ tract, other domains in ATXN1 are also involved in the initial events of protein aggregation such as a dimerization domain that promotes protein oligomerization. ATXN1 interacts with various proteins; among them, MED15 that significantly enhances the aggregation of the polyQ-expanded protein. Therefore, we set to identify the interaction site between ATXN1 and MED15 and assess whether its chemical targeting would affect polyQ protein aggregation. First, we predicted the structure of ATXN1 and MED15 and simulated their interaction. We experimentally validated that amino acids (aa) 99-163 of ATXN1 and aa548-665 of MED15 are critical for this protein-protein interaction (PPI). We also show that the aa99-163 domain in ATXN1 is involved in the dimerization of the mutant isoform. Targeting this domain with a chemical compound identified through virtual screening (Chembridge ID: 5755483) inhibited both the interaction of ATXN1 with MED15 and the dimerization of polyQ-expanded ATXN1. These results strengthen our assumption that the aa99-163 domain of ATXN1 may be involved in polyQ protein aggregation and highlight compound 5755483 as a potent first-in-class therapeutic agent for SCA1.
2023-11-01 | 60 Impact of Reducing the Nuclear Mutant ATXN1 on Spinocerebellar Ataxia-Like Phenotype
Objective: Spinocerebellar ataxia type one (SCA1) is an autosomal dominant neurodegenerative disease caused by an expanded CAG repeat that encodes glutamine (polyQ) in the affected ATXN1 gene. SCA1 pathology is commonly characterized by the degeneration of the cerebellar Purkinje cells (PC) and brainstem. Symptoms include motor dysfunction, cognitive impairments, bulbar dysfunction, and premature death. Atxn1 175Q/2Q knock-in mice were previously developed to model SCA1 by inserting 175 expanded CAG repeats into one allele of the Atxn1 gene, producing mice expressing ATXN1 throughout the brain and displaying SCA1 symptoms. Previous research has indicated the role of localization of the ATXN1 protein to the nucleus in pathology. Therefore, the Atxn1 175QK772T/2Q mouse model was created by disrupting the NLS in the expanded Atxn1 175Q/2Q mice by replacing lysine with threonine at position 772 in the nuclear localization sequence (NLS). Since this amino acid change previously blocked PC disease in another mouse model, the Atxn1 175QK772T/2Q mice were created to examine how the NLS mutation affects neuronal cells. RNA sequencing analysis was previously performed and found differentially expressed genes (DEG) with Atxn1 175Q/2Q downregulated compared to Atxn1 175QK772T/2Q and Atxn1 2Q/2Q in the cerebellum, medulla, cortex, hippocampus, and striatum. The aim was to analyze these brain regions to validate the RNAseq differential gene expression at a protein level. Participants and Methods: Therefore, western blots were performed on the following mouse models (n=12): wild type mice (Atxn1 2Q/2Q ), mice with the nuclear localization sequence mutation (Atxn1 2QK772T/2Q ), and mice with 175 expanded CAG repeats (Atxn1 175/2Q ). Based off the RNAseq data, the cerebellum was tested with ion channel genes (Cav3.1, Kcnma1, and Trpc3) and the striatum was tested with a gene found in medium-spiny neurons (DARPP-32). Results: In the cerebellum, Atxn1 175/2Q was significantly downregulated compared to Atxn1 175QK772T/2Q in Cav3.1, Trpc3, and Kcnma1. Atxn1 175Q/2Q was significantly downregulated compared to Atxn1 2Q/2Q in Trpc3 and Kcnma1. Atxn1 175QK772T/2Q was significantly downregulated compared to Atxn1 2Q/2Q in Trpc3. In the striatum, there was significantly reduced DARPP-32 expression found between Atxn1 2Q/2Q and Atxn1 175QK772T/2Q , Atxn1 2Q/2Q and Atxn1 175Q/2Q , and Atxn1 175Q/2Q and Atxn1 175QK772T/2Q . Conclusions: Therefore, the significantly reduced gene expression at the protein level in the cerebellum and striatum validate RNAseq differentially expressed genes. Additionally, the downregulation of both the Atxn1 175Q/2Q and Atxn1 175QK772TQ/2Q compared to Atxn1 2Q/2Q in the striatum supports the lack of learning of those mouse models on the rotarod, suggesting that the nuclear localization mutation does not rescue learning. Interestingly, the downregulation of Atxn1 175Q/2Q compared to Atxn1 175QK772TQ/2Q likely supports the age-related motor decline rescue in the rotarod seen in Atxn1 175QK772T/2Q and not Atxn1 175Q/2Q .
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.
2026-05-25 | 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.
2026-04-27 | Structural Mapping of Proteins Implicated in Rare Pediatric Genetic Disorders — Pediatric Research Dataset v1.0
Abstract This dataset presents curated structural sequences and disorder annotations for proteins implicated in rare pediatric genetic disorders, including MECP2 (Rett Syndrome), Ataxin-1 (Spinocerebellar Ataxia Type 1), Ataxin-3 (Machado-Joseph Disease/SCA3), and additional targets associated with inherited childhood pathologies. Each entry provides UniProt accession identifiers, intrinsic disorder classifications, and full-length amino acid sequences suitable for structural prediction, pharmacological chaperone design, and gene therapy target validation. This resource aims to support the development of precision interventions for conditions that disproportionately affect pediatric populations. Plain Language Summary Many rare childhood diseases are caused by inherited genetic mutations that produce misshapen, non-functional proteins. This dataset provides the detailed molecular sequences of proteins linked to conditions such as Rett Syndrome and spinocerebellar ataxia. By sharing this structural information openly, we help researchers study exactly how these proteins are malformed and explore potential treatments — such as drugs that help the proteins fold correctly or gene therapies that correct the underlying mutations — offering hope for children affected by these often-overlooked conditions. Related Resources Source Code: GitHub — Nexus Resonance Codex / Protein-Folding Author Profile: ORCID — James Paul Trageser Author: @jtrag on X
2026-04-14 | Long term administration of selective NMDA GluN2B receptor blocker Ro25-6981 attenuates neurodegeneration in mouse model of spinocerebellar ataxia type 1 (SCA1).
Spinocerebellar ataxia type 1 (SCA1) is caused by a CAG expansion in the gene that encodes the protein Ataxin1. Accumulation of the mutant protein in cells leads to degeneration of the cerebellum and brainstem, resulting in ataxia and culminates in failure of the circuits controlling swallowing and breathing. The nonselective NMDA receptor blocker memantine has been proposed as a potential treatment for SCA1, as it reduces excitotoxicity and neurodegeneration in other murine models of neurodegeneration. However, side effects of memantine limit its therapeutic potential, highlighting the need for more selective treatments. We have developed an SCA1 model where a lentiviral vector (LVV) selectively expresses mutant Ataxin1 in cerebellar astrocytes, triggering neuronal death through glial dysfunction and NMDA receptor-mediated excitotoxicity. Using this model, we investigate the effects of long-term administration of Ro25-6981, a selective blocker of the GluN2B subunit of glutamate receptors, typically found on extrasynaptic NMDA receptors. Chronic administration of Ro25-6981 (0.5 mg/kg day intraperitoneally) for 4 weeks prevented deterioration of motor activity in SCA1 model mice, an effect, associated with reduced neurodegeneration and decreased reactivity of Bergmann glia in the cerebellar cortex. Moreover, short-term endocannabinoid-mediated plasticity was partially preserved. Long-term blockade of NMDA receptors with Ro25-6981 caused a compensatory upregulation of expression of GluN2B and NR2A subunits. These findings suggest that specific targeting of extrasynaptic NMDA receptors with Ro25-6981 or similar drugs might offer a viable therapeutic strategy for treatment of SCA1.
2026-02-23 | Investigation of autophagy-activating molecules in a glia-specific Spinocerebellar ataxia type 1 model
Autophagy is a critical neuroprotective mechanism, the impairment of which can lead to severe neurodegenerative diseases. Spinocerebellar ataxia type 1 (SCA1) is a monogenic neurodegenerative disorder, characterised by the presence of protein aggregates and consequent loss of cellular functions. The expression of mutant Ataxin1 (ATXN1) in glial cells has been demonstrated to induce inflammatory responses and loss of supportive functions, thereby exacerbating neuronal degeneration in SCA1. Autophagic dysfunction has been shown to affect both neurons and glial cells, resulting in widespread pathological consequences. In this work, we aimed to evaluate the efficacy of two small-molecule autophagy activators, AUTEN-67 and AUTEN-99, in models of glia-specific SCA1 in Drosophila . Our results demonstrate that AUTEN-99 has a stronger autophagy enhancing effect, with significantly improved response times and survival rates, compared to untreated ATXN1 mutants. Glia-specific assays in mouse primary hippocampal cultures also confirmed that AUTEN-99 is a more effective activator. Ultimately, co-treatment of neuronal and glial cultures did not reveal any synergistic benefits from combining the two AUTEN compounds compared to single-agent treatment. Our findings contribute to a better understanding of the utility of AUTENs and may help to understand the critical role of autophagy in neurodegenerative diseases.
gene therapies
2026-03-19 | Neural basis for mutant ATAXIN-1 induced respiratory dysfunction in mouse models of spinocerebellar ataxia type 1.
Spinocerebellar ataxia type 1 is a neurodegenerative disease characterized by motor dysfunction and premature death usually from compromised swallowing and respiration. Using plethysmography, we characterized respiration in the conditional f-ATXN1146Q/2Q SCA1 model. We found a progressive elevation of baseline respiration that impairs ability of f-ATXN1146Q/2Q mice to increase breathing during challenge. To delineate regions contributing to respiratory dysfunction, f-ATXN1146Q/2Q mice were crossed with Nestin-Cre and Acta1-Cre mice, respectively. Respiration improved by removing mATXN1 from neural lineages, but not from skeletal muscle demonstrating mATXN1 in the central nervous system is a key driver of respiratory dysfunction in SCA1 mouse models. Moreover, respiratory dysfunction in SCA1 mice involves two aspects: behavioral dysregulation exhibited as increased movement during plethysmography, and functional dysregulation of respiratory circuitry. As both of these aspects are rescued by deleting mATXN1 from neural cells, we further investigated the role of cerebellar Purkinje cells and chemosensing neurons in the brain stem in SCA1 respiratory phenotype. Our results indicate complex multiregional etiology of respiratory dysfunction. Mechanistically we found that in contrast to most other SCA1 symptoms, nuclear localization of mATXN1 does not play a key role in respiratory dysfunction.
2025-12-11 | TMEM206 gene knockout improves balance performance in SCA1 transgenic mice.
TMEM206 was identified as a conserved chloride channel that underlies widely expressed, proton-activated, outwardly rectifying chloride currents. Spinocerebellar ataxia type 1 (SCA1) is one of polyglutamine diseases, and is characterized as a progressive and autosomal dominant genetic disease, which is caused by an increasing number of CAG repeats in the ataxin-1 gene. TMEM206 was confirmed to interact with ataxin-1. This study suggests that TMEM206-ataxin-1 interaction might involve in the pathological mechanisms of SCA1. To elucidate the mechanisms of SCA1 involved in proton-activated chloride channel gating, we bred TMEM206 knockout mice using SCA1 model mice. Motor coordination and balance in mice was evaluated using rotarod test and grip strength. These studies showed that genetic depletion of TMEM206 has slight impacts on the SCA1 mice weight, and partially improves motor incoordination in Atxn1154Q/2Q mice. No alteration in grip strength was found in Atxn1154Q/2Q mice with depletion of the TMEM206 gene. Our studies indicate that the TMEM206 knockout appears to emerge as a potential therapy method for SCA1 mice.
2024-12-03 | CRISPR/Cas9-induced double-strand breaks in the huntingtin locus lead to CAG repeat contraction through DNA end resection and homology-mediated repair
Abstract Background The expansion of CAG/CTG repeats in functionally unrelated genes is a causative factor in many inherited neurodegenerative disorders, including Huntington’s disease (HD), spinocerebellar ataxias (SCAs), and myotonic dystrophy type 1 (DM1). Despite many years of research, the mechanism responsible for repeat instability is unknown, and recent findings indicate the key role of DNA repair in this process. The repair of DSBs induced by genome editing tools results in the shortening of long CAG/CTG repeats in yeast models. Understanding this mechanism is the first step in developing a therapeutic strategy based on the controlled shortening of repeats. The aim of this study was to characterize Cas9-induced DSB repair products at the endogenous HTT locus in human cells and to identify factors affecting the formation of specific types of sequences. Results The location of the cleavage site and the surrounding sequence influence the outcome of DNA repair. DSBs within CAG repeats result in shortening of the repeats in frame in ~ 90% of products. The mechanism of this contraction involves MRE11-CTIP and RAD51 activity and DNA end resection. We demonstrated that a DSB located upstream of CAG repeats induces polymerase theta-mediated end joining, resulting in deletion of the entire CAG tract. Furthermore, using proteomic analysis, we identified novel factors that may be involved in CAG sequence repair. Conclusions Our study provides new insights into the complex mechanisms of CRISPR/Cas9-induced shortening of CAG repeats in human cells.
2024-11-14 | CRISPR-Cas9-directed gene therapy for spinocerebellar ataxia type 1
Spinocerebellar ataxia type 1 (SCA1) is a debilitating neurodegenerative disorder characterized by progressive motor dysfunction and cerebellar degeneration resulting from a CAG trinucleotide repeat expansion in the ATXN1 gene. Despite extensive research efforts, effective treatments remain elusive. Current interventions are limited to symptomatic management or transient knockdown of ATXN1 expression using antisense oligonucleotides and RNA interference, approaches that require repeated administration and rely on endogenous cellular mechanisms.1 The advent of CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats associated with CRISPR-associated protein 9) gene editing technology offers a transformative approach by enabling precise, long-lasting genomic modifications.
2024-09-24 | Cas9 editing of ATXN1 in a spinocerebellar ataxia type 1 mice and human iPSC-derived neurons.
Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disease caused by an expansion of the CAG repeat region of the ATXN1 gene. Currently there are no disease-modifying treatments; however, previous work has shown the potential of gene therapy, specifically RNAi, as a potential modality. Cas9 editing offers potential for these patients but has yet to be evaluated in SCA1 models. To test this, we first characterized the number of transgenes harbored in the common B05 mouse model of SCA1. Despite having five copies of the human mutant transgene, a 20% reduction of ATXN1 improved behavior deficits without increases in inflammatory markers. Importantly, the editing approach was confirmed in induced pluripotent stem cell (iPSC) neurons derived from patients with SCA1, promoting the translatability of the approach to patients.
oligonucleotides
2026-05-13 | A human Staufen1 BAC transgenic mouse exhibits abnormal autophagy and neurodegeneration across the central nervous system
RNA-binding proteins (RBPs) play an essential role in development, normal functioning, and human disease. Staufen1 (STAU1) is an RBP that regulates mRNA degradation and subcellular localization, and is part of the ATXN2 protein complex. Previously, we showed that STAU1 is overabundant in patient fibroblasts and in mouse models of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia type 2 (SCA2), where it is associated with impaired autophagic flux due to STAU1-mediated upregulation of mTOR translation. STAU1 overabundance and impaired autophagy cause accumulation of biomolecular condensates and abnormal unfolded protein response (UPR). We generated a mouse model expressing the entire human STAU1 gene (hSTAU1) in a bacterial artificial chromosome (BAC) construct. hSTAU1 in these mice was expressed in cerebral hemispheres, cerebellum, and spinal cord, as well as cultured cortical neurons and cortical and spinal cord astrocytes, and microglia. Expression of hSTAU1 caused dysregulated gene expression, abnormal autophagy, glial activation, and changes in neuronal marker proteins. All of these were significantly improved by reducing STAU1 abundance by RNAi, but exacerbated in BAC-STAU1 mice crossed with Prp-TDP-43(Q331K) transgenic mice. Similar results were also obtained in eye phenotypes in ALS- and SCA2-relevant fly models upon changing staufen-1 dosage. Despite the molecular changes, we observed no overt behavioral changes in mice up to 55 weeks of age, suggesting that STAU1 may function as an epistatic modifier of neuronal degeneration. The BAC-hSTAU1 mouse will be useful for developing therapies targeting the human STAU1 gene.
2025-12-30 | Translational Relevance of SCA1 Models for the Development of Therapies for Spinocerebellar Ataxia Type 1.
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative dis-ease caused by the expansion of cytosine-adenine-guanine (CAG) repeats in the ataxin-1 (ATXN1) gene, leading to toxic gain-of-function of the ataxin-1 (ATXN1) protein. This narrative review systematizes the clinical and genetic aspects of SCA1 and discusses key molecular and cellular mechanisms: the ATXN1-CIC ataxin-1-Capicua complex (ATXN1-CIC), the role of serine 776 (Ser776) phosphorylation, interactions with 14-3-3 proteins, transcriptional dysregulation, and critically analyzes experimental models of the disease in vivo and in vitro. In addition, it presents a descriptive quantitative analysis of the literature on in vivo SCA1 models, conducted using a defined search methodology with a cut-off date of 23 November 2025. For each model, phenotypic markers, molecular signatures, and applicability to preclinical testing tasks are summarized. A comparison of the models reveals their complementarity and outlines optimal research trajectories, including omics approaches and prospects for targeted antisense oligonucleotide (ASO) therapy, RNA interference (RNAi), and genome editing. The result is a practical guide for selecting a model in accordance with specific hypotheses and translational objectives.
2024-01-09 | Dysregulation of alternative splicing in spinocerebellar ataxia type 1.
Spinocerebellar ataxia type 1 is caused by an expansion of the polyglutamine tract in ATAXIN-1. Ataxin-1 is broadly expressed throughout the brain and is involved in regulating gene expression. However, it is not yet known if mutant ataxin-1 can impact the regulation of alternative splicing events. We performed RNA sequencing in mouse models of spinocerebellar ataxia type 1 and identified that mutant ataxin-1 expression abnormally leads to diverse splicing events in the mouse cerebellum of spinocerebellar ataxia type 1. We found that the diverse splicing events occurred in a predominantly cell autonomous manner. A majority of the transcripts with misregulated alternative splicing events were previously unknown, thus allowing us to identify overall new biological pathways that are distinctive to those affected by differential gene expression in spinocerebellar ataxia type 1. We also provide evidence that the splicing factor Rbfox1 mediates the effect of mutant ataxin-1 on misregulated alternative splicing and that genetic manipulation of Rbfox1 expression modifies neurodegenerative phenotypes in a Drosophila model of spinocerebellar ataxia type 1 in vivo. Together, this study provides novel molecular mechanistic insight into the pathogenesis of spinocerebellar ataxia type 1 and identifies potential therapeutic strategies for spinocerebellar ataxia type 1.
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.
2023-05-29 | Therapeutic Strategies for Spinocerebellar Ataxia Type 1.
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder that affects one or two individuals per 100,000. The disease is caused by an extended CAG repeat in exon 8 of the ATXN1 gene and is characterized mostly by a profound loss of cerebellar Purkinje cells, leading to disturbances in coordination, balance, and gait. At present, no curative treatment is available for SCA1. However, increasing knowledge on the cellular and molecular mechanisms of SCA1 has led the way towards several therapeutic strategies that can potentially slow disease progression. SCA1 therapeutics can be classified as genetic, pharmacological, and cell replacement therapies. These different therapeutic strategies target either the (mutant) ATXN1 RNA or the ataxin-1 protein, pathways that play an important role in downstream SCA1 disease mechanisms or which help restore cells that are lost due to SCA1 pathology. In this review, we will provide a summary of the different therapeutic strategies that are currently being investigated for SCA1.
other
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.
2019-12-06 | Motor Performances of Spontaneous and Genetically Modified Mutants with Cerebellar Atrophy.
Chance discovery of spontaneous mutants with atrophy of the cerebellar cortex has unearthed genes involved in optimizing motor coordination. Rotorod, stationary beam, and suspended wire tests are useful in delineating behavioral phenotypes of spontaneous mutants with cerebellar atrophy such as Grid2Lc, Grid2ho, Rorasg, Agtpbp1pcd, Relnrl, and Dab1scm. Likewise, transgenic or null mutants serving as experimental models of spinocerebellar ataxia (SCA) are phenotyped with the same tests. Among experimental models of autosomal dominant SCA, rotorod deficits were reported in SCA1 to 3, SCA5 to 8, SCA14, SCA17, and SCA27 and stationary beam deficits in SCA1 to 3, SCA5, SCA6, SCA13, SCA17, and SCA27. Beam tests are sensitive to experimental therapies of various kinds including molecules affecting glutamate signaling, mesenchymal stem cells, anti-oligomer antibodies, lentiviral vectors carrying genes, interfering RNAs, or neurotrophic factors, and interbreeding with other mutants.
2019-09-04 | Xenografting of human umbilical mesenchymal stem cells from Wharton’s jelly ameliorates mouse spinocerebellar ataxia type 1
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of CAG repeats in ATXN1 gene resulting in an expansion of polyglutamine repeats in the ATXN1 protein. Unfortunately, there has yet been any effective treatment so far for SCA1. This study investigated the feasibility of transplanting human umbilical mesenchymal stem cells (HUMSCs) into transgenic SCA1 mice containing an expanded uninterrupted allele with 82 repeats in the ATXN1-coding region.106 human umbilical mesenchymal stem cells were transplanted into the cerebella at 1 month of age.HUMSCs displayed significant ameliorating effects in SCA1 mice in terms of motor behaviors in balance beam test and open field test as compared with the untransplanted SCA1 mice. HUMSCs transplantation effectively reduced the cerebellar atrophy, salvaged Purkinje cell death, and alleviated molecular layer shrinkage. Electrophysiological studies showed higher amplitudes of compound motor action potentials as indicated by increasing neuronal-muscular response strength to stimuli after stem cell transplantation. At 5 months after transplantation, HUMSCs scattering in the mice cerebella remained viable and secreted cytokines without differentiating into neuronal or glia cells.Our findings provide hope for a new therapeutic direction for the treatment of SCA1.
2016-10-21 | Transplantation and Stem Cell Therapy for Cerebellar Degenerations.
Stem cell-based and regenerative therapy may become a hopeful treatment for neurodegenerative diseases including hereditary cerebellar degenerations. Neurotransplantation therapy mainly aims to substitute lost cells, but potential effects might include various mechanisms including nonspecific trophic effects and stimulation of endogenous regenerative processes and neural plasticity. Nevertheless, currently, there remain serious limitations. There is a wide spectrum of human hereditary cerebellar degenerations as well as numerous cerebellar mutant mouse strains that serve as models for the development of effective therapy. By now, transplantation has been shown to ameliorate cerebellar function, e.g. in Purkinje cell degeneration mice, Lurcher mutant mice and mouse models of spinocerebellar ataxia type 1 and type 2 and Niemann-Pick disease type C. Despite the lack of direct comparative studies, it appears that there might be differences in graft development and functioning between various types of cerebellar degeneration. Investigation of the relation of graft development to specific morphological, microvascular or biochemical features of the diseased host tissue in various cerebellar degenerations may help to identify factors determining the fate of grafted cells and potential of their functional integration.
2015-12-17 | Ataxin-1 oligomers induce local spread of pathology and decreasing them by passive immunization slows Spinocerebellar ataxia type 1 phenotypes
Previously, we reported that ATXN1 oligomers are the primary drivers of toxicity in Spinocerebellar ataxia type 1 (SCA1; Lasagna-Reeves et al., 2015). Here we report that polyQ ATXN1 oligomers can propagate locally in vivo in mice predisposed to SCA1 following intracerebral oligomeric tissue inoculation. Our data also show that targeting these oligomers with passive immunotherapy leads to some improvement in motor coordination in SCA1 mice and to a modest increase in their life span. These findings provide evidence that oligomer propagation is regionally limited in SCA1 and that immunotherapy targeting extracellular oligomers can mildly modify disease phenotypes.
proteins
2026-03-12 | Retrotransposition Events Shape the Evolution of the Ataxin-3 Gene Family in Primates.
Evolutionary studies of disease-associated genes provide crucial insights into pathological mechanisms and potential therapeutic targets. Polyglutamine spinocerebellar ataxias (SCAs) are human neurodegenerative diseases caused by toxic expanded CAG repeats. Studies on SCA1 have shown that a paralog of the causing-gene can partially rescue protein function and alleviate the neuropathology. The most common SCA, Machado-Joseph disease (MJD/SCA3), caused by mutated ataxin-3 gene (ATXN3), has no treatment currently available. Its paralog ataxin-3 like (ATXN3L) remains largely unexplored. Here, we identify three new retrotransposition events of ATXN3: ATXN3L0 in Euarchontoglires, ATXN3L2 in Simiformes, and ATXN3L3 in Cercopithecidae, in addition to ATXN3L (herein called ATXN3L1) originated in Haplorrhini. ATXN3 and ATXN3L1 are both under purifying selection throughout primate evolution, maintaining about 70% of amino acid identity. Also, the high conservation of ATXN3L1 Josephin domain hints at functional redundancy with the parental disease-associated ATXN3. ATXN3L2 presents a remarkable nucleotide similarity to ATXN3 (79%) in an interrupted reading frame, which may produce a regulatory RNA. Conversely, ATXN3L0 is likely a non-functional retrocopy and ATXN3L3 is absent in humans with no relevance for the disease. The comparison of (CAG)n interruption patterns of the different paralogs in several primates elucidates the process leading to the currently observed pure long tracts in human ATXN3, responsible for disease when expanded. This study intends to pioneer the identification of new paralogs of SCA-associated genes and the use of phylogenetic analyses to explore their potential role for targeted therapies.
2026-02-12 | Long-term efficacy and disease-specific responsiveness to protirelin in patients with spinocerebellar degeneration: A retrospective study
INTRODUCTION: 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. METHODS: 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). RESULTS: 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%). CONCLUSION: 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.
2025-10-02 | Spinocerebellar Ataxia Type 1 (SCA1) Cell Models Display Widespread Mitochondrial and Extra-Nuclear Alterations.
Ataxin-1 (ATXN1) is a nuclear-cytoplasmic shuttling protein, which, when expanded in its polyglutamine coding stretch, causes the progressive neurodegenerative disease Spinocerebellar Ataxia Type 1 (SCA1). While the role of nuclear ATXN1 as a repressor of transcription and regulator of splicing is well studied, its potential cytoplasmic role is more ambiguous. We previously demonstrated mitochondrial dysfunction- including altered respiration and enhanced oxidative stress- is associated with early SCA1 pathogenesis in mice. Moreover, intervention with the electron transport chain substrate succinic acid ameliorated Purkinje cell atrophy and cerebellar behavioral deficits. We now hypothesize that mitochondrial dysfunction in SCA1 may be at least partially due to cytoplasmic interactions between ATXN1 and mitochondria, rather than a result of mutant ATXN1's altered nuclear function. In order to characterize the extent of mitochondrial dysfunction due to mutant ATXN1, we turned to cerebellar-derived Daoy cells which endogenously express human wild type ATXN1. Our SCA1 Daoy model stably over-express phosphorylation-prone, nuclear-aggregating ATXN1[82]. Despite the short lifespan (~ 33 h), Daoy SCA1 cells reveal gross morphological, compositional, and physiological deficits. Conversely, expression in Daoy of a phosphorylation-resistant, cytoplasm-degradable, non-aggregating ATXN1 (ATXN1[82Q-A776]) selectively resulted in intermediate physiological phenotypes and altered mitochondrial protein composition. Finally, our meta-analysis of previously published data supports direct interactions between mutant polyglutamine-expanded ATXN1 and mitochondrial proteins involved in apoptosis, oxidative phosphorylation, composition, and transcription. Our data therefore suggest that irrespective of a disease context and ATXN1[82Q] nuclear aggregation, mitochondrial deficits occur. Overall, the results of this study show mutant ATXN1 can affect metabolic processes outside of its deleterious effect on transcription and splicing, and highlights its multifaceted and multicompartmental function.
2025-03-17 | Chemical targeting of the ATXN1 aa99-163 interaction site suppresses polyQ-expanded protein dimerization
ABSTRACT Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a polyglutamine (polyQ) tract in the ATXN1 protein. This expansion is thought to be responsible for the gradual aggregation of the mutant protein, which is associated with increased cytotoxicity and neuronal cell death. Apart from the polyQ tract, other domains in ATXN1 are also involved in the initial events of protein aggregation such as a dimerization domain that promotes protein oligomerization. ATXN1 interacts with various proteins; among them, MED15 that significantly enhances the aggregation of the polyQ-expanded protein. Therefore, we set to identify the interaction site between ATXN1 and MED15 and assess whether its chemical targeting would affect polyQ protein aggregation. First, we predicted the structure of ATXN1 and MED15 and simulated their interaction. We experimentally validated that amino acids (aa) 99-163 of ATXN1 and aa548-665 of MED15 are critical for this protein-protein interaction (PPI). We also show that the aa99-163 domain in ATXN1 is involved in the dimerization of the mutant isoform. Targeting this domain with a chemical compound identified through virtual screening (Chembridge ID: 5755483) inhibited both the interaction of ATXN1 with MED15 and the dimerization of polyQ-expanded ATXN1. These results strengthen our assumption that the aa99-163 domain of ATXN1 may be involved in polyQ protein aggregation and highlight compound 5755483 as a potent first-in-class therapeutic agent for SCA1.
2023-11-01 | 60 Impact of Reducing the Nuclear Mutant ATXN1 on Spinocerebellar Ataxia-Like Phenotype
Objective: Spinocerebellar ataxia type one (SCA1) is an autosomal dominant neurodegenerative disease caused by an expanded CAG repeat that encodes glutamine (polyQ) in the affected ATXN1 gene. SCA1 pathology is commonly characterized by the degeneration of the cerebellar Purkinje cells (PC) and brainstem. Symptoms include motor dysfunction, cognitive impairments, bulbar dysfunction, and premature death. Atxn1 175Q/2Q knock-in mice were previously developed to model SCA1 by inserting 175 expanded CAG repeats into one allele of the Atxn1 gene, producing mice expressing ATXN1 throughout the brain and displaying SCA1 symptoms. Previous research has indicated the role of localization of the ATXN1 protein to the nucleus in pathology. Therefore, the Atxn1 175QK772T/2Q mouse model was created by disrupting the NLS in the expanded Atxn1 175Q/2Q mice by replacing lysine with threonine at position 772 in the nuclear localization sequence (NLS). Since this amino acid change previously blocked PC disease in another mouse model, the Atxn1 175QK772T/2Q mice were created to examine how the NLS mutation affects neuronal cells. RNA sequencing analysis was previously performed and found differentially expressed genes (DEG) with Atxn1 175Q/2Q downregulated compared to Atxn1 175QK772T/2Q and Atxn1 2Q/2Q in the cerebellum, medulla, cortex, hippocampus, and striatum. The aim was to analyze these brain regions to validate the RNAseq differential gene expression at a protein level. Participants and Methods: Therefore, western blots were performed on the following mouse models (n=12): wild type mice (Atxn1 2Q/2Q ), mice with the nuclear localization sequence mutation (Atxn1 2QK772T/2Q ), and mice with 175 expanded CAG repeats (Atxn1 175/2Q ). Based off the RNAseq data, the cerebellum was tested with ion channel genes (Cav3.1, Kcnma1, and Trpc3) and the striatum was tested with a gene found in medium-spiny neurons (DARPP-32). Results: In the cerebellum, Atxn1 175/2Q was significantly downregulated compared to Atxn1 175QK772T/2Q in Cav3.1, Trpc3, and Kcnma1. Atxn1 175Q/2Q was significantly downregulated compared to Atxn1 2Q/2Q in Trpc3 and Kcnma1. Atxn1 175QK772T/2Q was significantly downregulated compared to Atxn1 2Q/2Q in Trpc3. In the striatum, there was significantly reduced DARPP-32 expression found between Atxn1 2Q/2Q and Atxn1 175QK772T/2Q , Atxn1 2Q/2Q and Atxn1 175Q/2Q , and Atxn1 175Q/2Q and Atxn1 175QK772T/2Q . Conclusions: Therefore, the significantly reduced gene expression at the protein level in the cerebellum and striatum validate RNAseq differentially expressed genes. Additionally, the downregulation of both the Atxn1 175Q/2Q and Atxn1 175QK772TQ/2Q compared to Atxn1 2Q/2Q in the striatum supports the lack of learning of those mouse models on the rotarod, suggesting that the nuclear localization mutation does not rescue learning. Interestingly, the downregulation of Atxn1 175Q/2Q compared to Atxn1 175QK772TQ/2Q likely supports the age-related motor decline rescue in the rotarod seen in Atxn1 175QK772T/2Q and not Atxn1 175Q/2Q .
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.
2026-05-25 | 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.
2026-04-27 | Structural Mapping of Proteins Implicated in Rare Pediatric Genetic Disorders — Pediatric Research Dataset v1.0
Abstract This dataset presents curated structural sequences and disorder annotations for proteins implicated in rare pediatric genetic disorders, including MECP2 (Rett Syndrome), Ataxin-1 (Spinocerebellar Ataxia Type 1), Ataxin-3 (Machado-Joseph Disease/SCA3), and additional targets associated with inherited childhood pathologies. Each entry provides UniProt accession identifiers, intrinsic disorder classifications, and full-length amino acid sequences suitable for structural prediction, pharmacological chaperone design, and gene therapy target validation. This resource aims to support the development of precision interventions for conditions that disproportionately affect pediatric populations. Plain Language Summary Many rare childhood diseases are caused by inherited genetic mutations that produce misshapen, non-functional proteins. This dataset provides the detailed molecular sequences of proteins linked to conditions such as Rett Syndrome and spinocerebellar ataxia. By sharing this structural information openly, we help researchers study exactly how these proteins are malformed and explore potential treatments — such as drugs that help the proteins fold correctly or gene therapies that correct the underlying mutations — offering hope for children affected by these often-overlooked conditions. Related Resources Source Code: GitHub — Nexus Resonance Codex / Protein-Folding Author Profile: ORCID — James Paul Trageser Author: @jtrag on X
2026-04-14 | Long term administration of selective NMDA GluN2B receptor blocker Ro25-6981 attenuates neurodegeneration in mouse model of spinocerebellar ataxia type 1 (SCA1).
Spinocerebellar ataxia type 1 (SCA1) is caused by a CAG expansion in the gene that encodes the protein Ataxin1. Accumulation of the mutant protein in cells leads to degeneration of the cerebellum and brainstem, resulting in ataxia and culminates in failure of the circuits controlling swallowing and breathing. The nonselective NMDA receptor blocker memantine has been proposed as a potential treatment for SCA1, as it reduces excitotoxicity and neurodegeneration in other murine models of neurodegeneration. However, side effects of memantine limit its therapeutic potential, highlighting the need for more selective treatments. We have developed an SCA1 model where a lentiviral vector (LVV) selectively expresses mutant Ataxin1 in cerebellar astrocytes, triggering neuronal death through glial dysfunction and NMDA receptor-mediated excitotoxicity. Using this model, we investigate the effects of long-term administration of Ro25-6981, a selective blocker of the GluN2B subunit of glutamate receptors, typically found on extrasynaptic NMDA receptors. Chronic administration of Ro25-6981 (0.5 mg/kg day intraperitoneally) for 4 weeks prevented deterioration of motor activity in SCA1 model mice, an effect, associated with reduced neurodegeneration and decreased reactivity of Bergmann glia in the cerebellar cortex. Moreover, short-term endocannabinoid-mediated plasticity was partially preserved. Long-term blockade of NMDA receptors with Ro25-6981 caused a compensatory upregulation of expression of GluN2B and NR2A subunits. These findings suggest that specific targeting of extrasynaptic NMDA receptors with Ro25-6981 or similar drugs might offer a viable therapeutic strategy for treatment of SCA1.
2026-02-23 | Investigation of autophagy-activating molecules in a glia-specific Spinocerebellar ataxia type 1 model
Autophagy is a critical neuroprotective mechanism, the impairment of which can lead to severe neurodegenerative diseases. Spinocerebellar ataxia type 1 (SCA1) is a monogenic neurodegenerative disorder, characterised by the presence of protein aggregates and consequent loss of cellular functions. The expression of mutant Ataxin1 (ATXN1) in glial cells has been demonstrated to induce inflammatory responses and loss of supportive functions, thereby exacerbating neuronal degeneration in SCA1. Autophagic dysfunction has been shown to affect both neurons and glial cells, resulting in widespread pathological consequences. In this work, we aimed to evaluate the efficacy of two small-molecule autophagy activators, AUTEN-67 and AUTEN-99, in models of glia-specific SCA1 in Drosophila . Our results demonstrate that AUTEN-99 has a stronger autophagy enhancing effect, with significantly improved response times and survival rates, compared to untreated ATXN1 mutants. Glia-specific assays in mouse primary hippocampal cultures also confirmed that AUTEN-99 is a more effective activator. Ultimately, co-treatment of neuronal and glial cultures did not reveal any synergistic benefits from combining the two AUTEN compounds compared to single-agent treatment. Our findings contribute to a better understanding of the utility of AUTENs and may help to understand the critical role of autophagy in neurodegenerative diseases.
gene therapies
2026-03-19 | Neural basis for mutant ATAXIN-1 induced respiratory dysfunction in mouse models of spinocerebellar ataxia type 1.
Spinocerebellar ataxia type 1 is a neurodegenerative disease characterized by motor dysfunction and premature death usually from compromised swallowing and respiration. Using plethysmography, we characterized respiration in the conditional f-ATXN1146Q/2Q SCA1 model. We found a progressive elevation of baseline respiration that impairs ability of f-ATXN1146Q/2Q mice to increase breathing during challenge. To delineate regions contributing to respiratory dysfunction, f-ATXN1146Q/2Q mice were crossed with Nestin-Cre and Acta1-Cre mice, respectively. Respiration improved by removing mATXN1 from neural lineages, but not from skeletal muscle demonstrating mATXN1 in the central nervous system is a key driver of respiratory dysfunction in SCA1 mouse models. Moreover, respiratory dysfunction in SCA1 mice involves two aspects: behavioral dysregulation exhibited as increased movement during plethysmography, and functional dysregulation of respiratory circuitry. As both of these aspects are rescued by deleting mATXN1 from neural cells, we further investigated the role of cerebellar Purkinje cells and chemosensing neurons in the brain stem in SCA1 respiratory phenotype. Our results indicate complex multiregional etiology of respiratory dysfunction. Mechanistically we found that in contrast to most other SCA1 symptoms, nuclear localization of mATXN1 does not play a key role in respiratory dysfunction.
2025-12-11 | TMEM206 gene knockout improves balance performance in SCA1 transgenic mice.
TMEM206 was identified as a conserved chloride channel that underlies widely expressed, proton-activated, outwardly rectifying chloride currents. Spinocerebellar ataxia type 1 (SCA1) is one of polyglutamine diseases, and is characterized as a progressive and autosomal dominant genetic disease, which is caused by an increasing number of CAG repeats in the ataxin-1 gene. TMEM206 was confirmed to interact with ataxin-1. This study suggests that TMEM206-ataxin-1 interaction might involve in the pathological mechanisms of SCA1. To elucidate the mechanisms of SCA1 involved in proton-activated chloride channel gating, we bred TMEM206 knockout mice using SCA1 model mice. Motor coordination and balance in mice was evaluated using rotarod test and grip strength. These studies showed that genetic depletion of TMEM206 has slight impacts on the SCA1 mice weight, and partially improves motor incoordination in Atxn1154Q/2Q mice. No alteration in grip strength was found in Atxn1154Q/2Q mice with depletion of the TMEM206 gene. Our studies indicate that the TMEM206 knockout appears to emerge as a potential therapy method for SCA1 mice.
2024-12-03 | CRISPR/Cas9-induced double-strand breaks in the huntingtin locus lead to CAG repeat contraction through DNA end resection and homology-mediated repair
Abstract Background The expansion of CAG/CTG repeats in functionally unrelated genes is a causative factor in many inherited neurodegenerative disorders, including Huntington’s disease (HD), spinocerebellar ataxias (SCAs), and myotonic dystrophy type 1 (DM1). Despite many years of research, the mechanism responsible for repeat instability is unknown, and recent findings indicate the key role of DNA repair in this process. The repair of DSBs induced by genome editing tools results in the shortening of long CAG/CTG repeats in yeast models. Understanding this mechanism is the first step in developing a therapeutic strategy based on the controlled shortening of repeats. The aim of this study was to characterize Cas9-induced DSB repair products at the endogenous HTT locus in human cells and to identify factors affecting the formation of specific types of sequences. Results The location of the cleavage site and the surrounding sequence influence the outcome of DNA repair. DSBs within CAG repeats result in shortening of the repeats in frame in ~ 90% of products. The mechanism of this contraction involves MRE11-CTIP and RAD51 activity and DNA end resection. We demonstrated that a DSB located upstream of CAG repeats induces polymerase theta-mediated end joining, resulting in deletion of the entire CAG tract. Furthermore, using proteomic analysis, we identified novel factors that may be involved in CAG sequence repair. Conclusions Our study provides new insights into the complex mechanisms of CRISPR/Cas9-induced shortening of CAG repeats in human cells.
2024-11-14 | CRISPR-Cas9-directed gene therapy for spinocerebellar ataxia type 1
Spinocerebellar ataxia type 1 (SCA1) is a debilitating neurodegenerative disorder characterized by progressive motor dysfunction and cerebellar degeneration resulting from a CAG trinucleotide repeat expansion in the ATXN1 gene. Despite extensive research efforts, effective treatments remain elusive. Current interventions are limited to symptomatic management or transient knockdown of ATXN1 expression using antisense oligonucleotides and RNA interference, approaches that require repeated administration and rely on endogenous cellular mechanisms.1 The advent of CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats associated with CRISPR-associated protein 9) gene editing technology offers a transformative approach by enabling precise, long-lasting genomic modifications.
2024-09-24 | Cas9 editing of ATXN1 in a spinocerebellar ataxia type 1 mice and human iPSC-derived neurons.
Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disease caused by an expansion of the CAG repeat region of the ATXN1 gene. Currently there are no disease-modifying treatments; however, previous work has shown the potential of gene therapy, specifically RNAi, as a potential modality. Cas9 editing offers potential for these patients but has yet to be evaluated in SCA1 models. To test this, we first characterized the number of transgenes harbored in the common B05 mouse model of SCA1. Despite having five copies of the human mutant transgene, a 20% reduction of ATXN1 improved behavior deficits without increases in inflammatory markers. Importantly, the editing approach was confirmed in induced pluripotent stem cell (iPSC) neurons derived from patients with SCA1, promoting the translatability of the approach to patients.
oligonucleotides
2026-05-13 | A human Staufen1 BAC transgenic mouse exhibits abnormal autophagy and neurodegeneration across the central nervous system
RNA-binding proteins (RBPs) play an essential role in development, normal functioning, and human disease. Staufen1 (STAU1) is an RBP that regulates mRNA degradation and subcellular localization, and is part of the ATXN2 protein complex. Previously, we showed that STAU1 is overabundant in patient fibroblasts and in mouse models of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia type 2 (SCA2), where it is associated with impaired autophagic flux due to STAU1-mediated upregulation of mTOR translation. STAU1 overabundance and impaired autophagy cause accumulation of biomolecular condensates and abnormal unfolded protein response (UPR). We generated a mouse model expressing the entire human STAU1 gene (hSTAU1) in a bacterial artificial chromosome (BAC) construct. hSTAU1 in these mice was expressed in cerebral hemispheres, cerebellum, and spinal cord, as well as cultured cortical neurons and cortical and spinal cord astrocytes, and microglia. Expression of hSTAU1 caused dysregulated gene expression, abnormal autophagy, glial activation, and changes in neuronal marker proteins. All of these were significantly improved by reducing STAU1 abundance by RNAi, but exacerbated in BAC-STAU1 mice crossed with Prp-TDP-43(Q331K) transgenic mice. Similar results were also obtained in eye phenotypes in ALS- and SCA2-relevant fly models upon changing staufen-1 dosage. Despite the molecular changes, we observed no overt behavioral changes in mice up to 55 weeks of age, suggesting that STAU1 may function as an epistatic modifier of neuronal degeneration. The BAC-hSTAU1 mouse will be useful for developing therapies targeting the human STAU1 gene.
2025-12-30 | Translational Relevance of SCA1 Models for the Development of Therapies for Spinocerebellar Ataxia Type 1.
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative dis-ease caused by the expansion of cytosine-adenine-guanine (CAG) repeats in the ataxin-1 (ATXN1) gene, leading to toxic gain-of-function of the ataxin-1 (ATXN1) protein. This narrative review systematizes the clinical and genetic aspects of SCA1 and discusses key molecular and cellular mechanisms: the ATXN1-CIC ataxin-1-Capicua complex (ATXN1-CIC), the role of serine 776 (Ser776) phosphorylation, interactions with 14-3-3 proteins, transcriptional dysregulation, and critically analyzes experimental models of the disease in vivo and in vitro. In addition, it presents a descriptive quantitative analysis of the literature on in vivo SCA1 models, conducted using a defined search methodology with a cut-off date of 23 November 2025. For each model, phenotypic markers, molecular signatures, and applicability to preclinical testing tasks are summarized. A comparison of the models reveals their complementarity and outlines optimal research trajectories, including omics approaches and prospects for targeted antisense oligonucleotide (ASO) therapy, RNA interference (RNAi), and genome editing. The result is a practical guide for selecting a model in accordance with specific hypotheses and translational objectives.
2024-01-09 | Dysregulation of alternative splicing in spinocerebellar ataxia type 1.
Spinocerebellar ataxia type 1 is caused by an expansion of the polyglutamine tract in ATAXIN-1. Ataxin-1 is broadly expressed throughout the brain and is involved in regulating gene expression. However, it is not yet known if mutant ataxin-1 can impact the regulation of alternative splicing events. We performed RNA sequencing in mouse models of spinocerebellar ataxia type 1 and identified that mutant ataxin-1 expression abnormally leads to diverse splicing events in the mouse cerebellum of spinocerebellar ataxia type 1. We found that the diverse splicing events occurred in a predominantly cell autonomous manner. A majority of the transcripts with misregulated alternative splicing events were previously unknown, thus allowing us to identify overall new biological pathways that are distinctive to those affected by differential gene expression in spinocerebellar ataxia type 1. We also provide evidence that the splicing factor Rbfox1 mediates the effect of mutant ataxin-1 on misregulated alternative splicing and that genetic manipulation of Rbfox1 expression modifies neurodegenerative phenotypes in a Drosophila model of spinocerebellar ataxia type 1 in vivo. Together, this study provides novel molecular mechanistic insight into the pathogenesis of spinocerebellar ataxia type 1 and identifies potential therapeutic strategies for spinocerebellar ataxia type 1.
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.
2023-05-29 | Therapeutic Strategies for Spinocerebellar Ataxia Type 1.
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder that affects one or two individuals per 100,000. The disease is caused by an extended CAG repeat in exon 8 of the ATXN1 gene and is characterized mostly by a profound loss of cerebellar Purkinje cells, leading to disturbances in coordination, balance, and gait. At present, no curative treatment is available for SCA1. However, increasing knowledge on the cellular and molecular mechanisms of SCA1 has led the way towards several therapeutic strategies that can potentially slow disease progression. SCA1 therapeutics can be classified as genetic, pharmacological, and cell replacement therapies. These different therapeutic strategies target either the (mutant) ATXN1 RNA or the ataxin-1 protein, pathways that play an important role in downstream SCA1 disease mechanisms or which help restore cells that are lost due to SCA1 pathology. In this review, we will provide a summary of the different therapeutic strategies that are currently being investigated for SCA1.
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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.
2019-12-06 | Motor Performances of Spontaneous and Genetically Modified Mutants with Cerebellar Atrophy.
Chance discovery of spontaneous mutants with atrophy of the cerebellar cortex has unearthed genes involved in optimizing motor coordination. Rotorod, stationary beam, and suspended wire tests are useful in delineating behavioral phenotypes of spontaneous mutants with cerebellar atrophy such as Grid2Lc, Grid2ho, Rorasg, Agtpbp1pcd, Relnrl, and Dab1scm. Likewise, transgenic or null mutants serving as experimental models of spinocerebellar ataxia (SCA) are phenotyped with the same tests. Among experimental models of autosomal dominant SCA, rotorod deficits were reported in SCA1 to 3, SCA5 to 8, SCA14, SCA17, and SCA27 and stationary beam deficits in SCA1 to 3, SCA5, SCA6, SCA13, SCA17, and SCA27. Beam tests are sensitive to experimental therapies of various kinds including molecules affecting glutamate signaling, mesenchymal stem cells, anti-oligomer antibodies, lentiviral vectors carrying genes, interfering RNAs, or neurotrophic factors, and interbreeding with other mutants.
2019-09-04 | Xenografting of human umbilical mesenchymal stem cells from Wharton’s jelly ameliorates mouse spinocerebellar ataxia type 1
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of CAG repeats in ATXN1 gene resulting in an expansion of polyglutamine repeats in the ATXN1 protein. Unfortunately, there has yet been any effective treatment so far for SCA1. This study investigated the feasibility of transplanting human umbilical mesenchymal stem cells (HUMSCs) into transgenic SCA1 mice containing an expanded uninterrupted allele with 82 repeats in the ATXN1-coding region.106 human umbilical mesenchymal stem cells were transplanted into the cerebella at 1 month of age.HUMSCs displayed significant ameliorating effects in SCA1 mice in terms of motor behaviors in balance beam test and open field test as compared with the untransplanted SCA1 mice. HUMSCs transplantation effectively reduced the cerebellar atrophy, salvaged Purkinje cell death, and alleviated molecular layer shrinkage. Electrophysiological studies showed higher amplitudes of compound motor action potentials as indicated by increasing neuronal-muscular response strength to stimuli after stem cell transplantation. At 5 months after transplantation, HUMSCs scattering in the mice cerebella remained viable and secreted cytokines without differentiating into neuronal or glia cells.Our findings provide hope for a new therapeutic direction for the treatment of SCA1.
2016-10-21 | Transplantation and Stem Cell Therapy for Cerebellar Degenerations.
Stem cell-based and regenerative therapy may become a hopeful treatment for neurodegenerative diseases including hereditary cerebellar degenerations. Neurotransplantation therapy mainly aims to substitute lost cells, but potential effects might include various mechanisms including nonspecific trophic effects and stimulation of endogenous regenerative processes and neural plasticity. Nevertheless, currently, there remain serious limitations. There is a wide spectrum of human hereditary cerebellar degenerations as well as numerous cerebellar mutant mouse strains that serve as models for the development of effective therapy. By now, transplantation has been shown to ameliorate cerebellar function, e.g. in Purkinje cell degeneration mice, Lurcher mutant mice and mouse models of spinocerebellar ataxia type 1 and type 2 and Niemann-Pick disease type C. Despite the lack of direct comparative studies, it appears that there might be differences in graft development and functioning between various types of cerebellar degeneration. Investigation of the relation of graft development to specific morphological, microvascular or biochemical features of the diseased host tissue in various cerebellar degenerations may help to identify factors determining the fate of grafted cells and potential of their functional integration.
2015-12-17 | Ataxin-1 oligomers induce local spread of pathology and decreasing them by passive immunization slows Spinocerebellar ataxia type 1 phenotypes
Previously, we reported that ATXN1 oligomers are the primary drivers of toxicity in Spinocerebellar ataxia type 1 (SCA1; Lasagna-Reeves et al., 2015). Here we report that polyQ ATXN1 oligomers can propagate locally in vivo in mice predisposed to SCA1 following intracerebral oligomeric tissue inoculation. Our data also show that targeting these oligomers with passive immunotherapy leads to some improvement in motor coordination in SCA1 mice and to a modest increase in their life span. These findings provide evidence that oligomer propagation is regionally limited in SCA1 and that immunotherapy targeting extracellular oligomers can mildly modify disease phenotypes.
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Drug Discovery Landscape
2 orphan drug designations for Spinocerebellar ataxia type 1.
2 orphan drug designations for Spinocerebellar ataxia type 1.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
a single stranded 2-methoxyethyl RNA nucleotide with a full-length phosphorothioate backbone | oligonucleotides | FDA | — | Cure Rare Disease |
stemchymal | cell therapies | FDA | Steminent Biotherapeutics, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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