RARE DISEASE
Autosomal dominant cerebellar ataxia
Autosomal dominant cerebellar ataxia
Autosomal dominant cerebellar ataxia
Synonyms: ADCA, Autosomal dominant spinocerebellar ataxia
Synonyms: ADCA, Autosomal dominant spinocerebellar ataxia
Synonyms: ADCA, Autosomal dominant spinocerebellar ataxia
Drug discovery
16
drugs
With orphan designations
Overview
Autosomal dominant cerebellar ataxia (ADCA) encompasses genetically heterogeneous neurodegenerative disorders characterized by progressive cerebellar dysfunction (gait ataxia, dysarthria, oculomotor deficits) and variable extracerebellar features. Classified into ADCA types I-IV, it includes spinocerebellar ataxias (SCAs) with subtypes involving retinal degeneration, brainstem involvement, or pure cerebellar pathology. Neurodegeneration stems primarily from polyglutamine expansions, RNA toxicity, or channelopathies, leading to multisystem neuronal loss [1][2][4][5].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
290 drug discovery papers about Autosomal dominant cerebellar ataxia, with 4 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
290 drug discovery papers about Autosomal dominant cerebellar ataxia, with 4 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-11 | Spinocerebellar ataxia 27B (FGF14 repeat expansion): Clinical spectrum, diagnostic pitfalls, and implications for late-onset ataxia
Abstract Spinocerebellar ataxia 27B (SCA27B; OMIM 620174) is an autosomal dominant late-onset cerebellar ataxia (LOCA) caused by intronic GAA repeat expansions in FGF14 , first described in 2023. Since its discovery, SCA27B has emerged as a major genetic cause of previously unexplained LOCA across multiple populations. We conducted a narrative review following the Scale for the Assessment of Narrative Review Articles (SANRA) guidance. PubMed, Embase, and Scopus were searched from January 2022 to April 2026 using terms related to SCA27B, FGF14 , GAA repeat expansions, downbeat nystagmus, and aminopyridine therapy. Reference lists of key studies were hand-searched. Human peer-reviewed studies were included, and evidence was synthesized qualitatively by domain. SCA27B typically presents with slowly progressive cerebellar ataxia, prominent downbeat nystagmus, and episodic symptoms such as vertigo, oscillopsia, and transient ataxia that may precede fixed deficits by years. These features are important diagnostic clues in patients otherwise labeled as having idiopathic ataxia or multiple system atrophy of cerebellar type. Prevalence among unsolved LOCA cohorts varies geographically, ranging from 1.2–1.3% in Japan and 1.83% in India to 15–30% in Europe and up to 60% in French-Canadians because of a founder effect. SCA27B is clinically actionable, as many patients experience symptomatic improvement with aminopyridines, particularly 4-aminopyridine. However, evidence remains observational, with no randomized controlled trials available. We review the genetics, epidemiology, clinical spectrum, imaging findings, differential diagnosis, and management of SCA27B, and support routine FGF14 testing in patients with unexplained late-onset ataxia, downbeat nystagmus, or episodic cerebellar symptoms.
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.
2026-05-23 | Rad23b exacerbates pathological aggregates through disrupting proteasome functions in Spinocerebellar ataxia type 3.
Spinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant ataxia globally, caused by expanded CAG repeats in the ATXN3 gene and consequent pathogenic accumulation of mutant ATXN3 (mATXN3) aggregates. The formation of these aggregates perturbs neuronal functions and leads to progressive neurodegeneration, yet the molecular mechanisms controlling mATXN3 proteostasis remain incompletely understood. Here, we identify RAD23 homolog B (Rad23b), a ubiquitin-binding shuttle factor, as a potential regulator of mATXN3 aggregates and toxicity upon high throughput proteomic analysis. Functional assays reveal that Rad23b overexpression enhances, while Rad23b knockdown or knockout reduces, mATXN3 aggregates and neuronal cell death. Mechanistically, Rad23b directly interacts with mATXN3, promotes its ubiquitination, and facilitates its delivery to the proteasome. Paradoxically, Rad23b disrupts proteasome catalytic activity, preventing mATXN3 degradation and exacerbating aggregate formation. Immunohistochemical analysis in SCA3 transgenic mice confirms colocalization of Rad23b with mATXN3 aggregates in cerebellar neurons. These findings highlight Rad23b as a crucial modulator of mATXN3 proteostasis, and imply Rad23b as a potential therapeutic target in SCA3.
2026-05-08 | Role of nuclear transport receptor KPNB1 in the pathophysiology of spinocerebellar ataxia type 3
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is the most common form of autosomal dominant hereditary ataxias and characterized by a pathological expansion of the polyglutamine (polyQ) tract within the ataxin-3 protein. Ataxin- 3 is mainly a cytoplasmic protein, although polyQ-expanded ataxin-3 accumulates in the nucleus of affected neurons and forms intranuclear aggregates, leading to neurotoxicity and cell death. Unravelling the underlying mechanisms in the nuclear localization of polyQ- expanded ataxin-3 and its involvement in neurotoxicity can provide insight into the pathogenesis of this disease and the development of novel therapeutic strategies. In this respect, investigation of the nucleocytoplasmic transport machinery and its implication for the pathogenesis of SCA3 and other polyQ diseases has gathered attention. Our lab has previously indicated the critical importance of karyopherin α-3 (KPNA3), a nuclear transport receptor, in the nuclear transport of ataxin-3 and its implication in the pathogenesis of SCA3. Since KPNA3 functions as an adaptor protein for karyopherin β-1 (KPNB1) in the nuclear transport of protein cargos, we aimed to explore the role of KPNB1 in the pathogenesis of SCA3 as well. Here, we report on SCA3 cell model-based analysis of the nuclear transport receptor KPNB1 and its implications for the pathogenesis of SCA3. We figured out that KPNB1 interacts directly with both wild-type and polyQ-expanded ataxin-3. However, modulating KPNB1 levels did not change the subcellular distribution of ataxin-3. Interestingly, KPNB1 overexpression reduced protein levels and aggregation of ataxin-3 and promoted its cleavage, whereas its knockdown and pharmacological inhibition led to an increase in soluble and insoluble levels of ataxin-3. Our data revealed that modulation of ataxin-3 was apparently based on protein fragmentation, independent of the classical SCA3-associated proteolytic pathways. Label-free quantitative proteomics and knockdown experiments indicated mitochondrial protease CLPP as a potential mediator of the ataxin-3-degrading effect induced by KPNB1 overexpression. We confirmed a reduction of KPNB1 protein levels in SCA3 by analyzing two SCA3 transgenic mouse models and induced pluripotent stem cells (iPSCs) derived from SCA3 patients. Our findings suggested a yet undescribed regulatory function of KPNB1 in modulating ataxin-3, thereby highlighting a new potential target of therapeutic value for SCA3.
2026-03-10 | Computational screening of natural small molecules as dual ATXN3 and LC3 binders for an autophagy-based strategy in spinocerebellar ataxia type 3
Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the ATXN3 gene, producing a polyglutamine expanded ataxin‑3 protein that misfolds, aggregates, and drives progressive neurodegeneration. Enhancing the selective autophagic clearance of mutant ATXN3 through recruitment to the autophagy adaptor LC3 on autophagosomal membranes represents a promising disease-modifying strategy. This study investigates whether natural small molecules can act as dual binders of ATXN3 and LC3, providing accessible scaffolds for an autophagy-based therapeutic approach in SCA3. The Josephin domain of human ATXN3 and human LC3 were prepared as receptor structures. Five natural ligands, quercetin, kaempferol, luteolin, rutin, and trehalose, were subjected to Vina-based molecular docking. For each ligand-target pair, the lowest energy pose was selected and analyzed for predicted binding free energies (ΔG, kcal/mol), hydrogen bond networks, and hydrophobic contacts. Pharmacokinetic properties were evaluated using SwissADME to assess drug likeness and oral bioavailability. Quercetin, kaempferol, and luteolin showed strong and balanced predicted binding to ATXN3 (-8.5 to -8.1 kcal/mol) and LC3 (-8.4 to -8.3 kcal/mol), with molecular weights 286-302 g/mol, high predicted gastrointestinal absorption, and no Lipinski violations. Rutin and trehalose bound ATXN3 weakly (-6.4 and -5.2 kcal/mol, respectively) but displayed strong ending to LC3 (-10.3 and -7.8 kcal/mol), though with poor oral drug-like properties (MW 610.52 and 342.30 g/mol, respectively, low gastrointestinal absorption and multiple Lipinski violations. Common natural flavonoids, particularly quercetin, kaempferol, and luteolin, exhibit strong dual-target binding with favorable oral drug-like properties, supporting their potential as simple scaffolds for autophagy-based therapeutic strategies in SCA3. These findings provide a clear rationale for subsequent biochemical and cellular validation of their ATTEC like mechanisms.
proteins
2025-04-28 | Restoration of Shal/KV4 proteostasis and motor function in a Drosophila model of spinocerebellar ataxia type 19/22.
Loss-of-function mutations in the human KCND3 gene encoding KV4.3 K+ channels are linked to the autosomal dominant neurodegenerative disease spinocerebellar ataxia type 19/22 (SCA19/22). Previous biophysical and biochemical analyses in vitro support the notion that the autosomal dominant inheritance pattern of SCA19/22 is associated with the dominant-negative effects of disease-causing KV4.3 mutants on proteostasis of their wild-type (WT) counterpart. Herein we aimed to explore whether the disease-causing mutants might perturb protein expression of endogenous KV4.3 channel in human cells, as well as contributing to in vivo pathomechanisms underlying motor impairments and neurodegeneration in an animal model of SCA19/22. Substantial reduction in human KV4.3 protein level was validated in skin fibroblasts derived from heterozygous SCA19/22 patients. Genetic knockdown of endogenous Shal, the fly ortholog of human KV4.3, in Drosophila led to locomotor impairment, ommatidia degeneration, and reduced brain cortex thickness, all of which was effectively ameliorated by transgenic expression of human KV4.3, but not KV1.1 K+ channel. Transgenic expression of SCA19/22-causing human KV4.3 mutants resulted in notable disruption of endogenous Shal proteostasis, locomotor function, and ommatidia morphology in Drosophila. Enhanced expression of the Drosophila molecular chaperones HSC70 and HSP83 in our fly model of SCA19/22 corrected Shal protein deficit, locomotor dysfunction, and neurodegeneration. Overexpression of Hsp90β also upregulated endogenous human KV4.3 protein level in patient-derived skin fibroblasts. Our findings highlight Drosophila as a suitable animal model for studying KV4.3 channelopathy in vivo, and accentuate a critical role of defective KV4.3 proteostasis in the pathogenesis of motor dysfunction and neurodegeneration in SCA19/22.
2025-03-27 | Functional characterization of two KCND3 variants associated with SCA 19/22 ataxia in Latin American families.
Spinocerebellar ataxia 19/22 (SCA19/22) represents a rare autosomal dominant genetic disorder resulting in progressive ataxia and cerebellar atrophy. SCA19/22 is caused by variants in the KCND3 gene, which encodes a voltage-gated potassium channel subunit essential for cerebellar Purkinje cell function. To date, 22 variants have been reported worldwide, with incomplete functional studies. We present four Chilean and Mexican cases in whom two single-nucleotide variants were identified through whole-exome sequencing of the probands. One variant (G371R) was initially cataloged as pathogenic and the other (S357W) as likely pathogenic according to the American College of Medical Genetics and Genomics criteria. The pathogenicity of the G371R variation was confirmed by in-silico mutagenesis. Our molecular models, that include electrostatic potential analysis and algorithms to analyze the pore dimensions (HOLE), indicated that the longer side chain of the arginine narrowed the channel's selectivity filter, while the positive charge modified its surface electrostatic potential, presumably preventing potassium flux. Functional characterization of the S357W variant was performed in AD293 cells. When overexpressed, KV4.3S357W channels alone showed no current. Protein electrophoresis revealed that the total number of KV4.3 channels expressed did not differ between the wild-type and mutated phenotypes, suggesting a protein trafficking malfunction. Co-expression of the KChIP2 auxiliary subunit partially rescued the potassium currents when the variant was expressed, albeit with very different biophysical characteristics, including faster inactivation vs. wild-type channels. This functional characterization of two KCND3 variants associated with SCA19/22 adds new evidence for the pathogenic role of Kv4.3 loss-of-function mutations and establishes a correlation between functional dominance and clinical severity in SCA19/22.
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 .
2021-07-26 | Transcriptomic and Metabolic Network Analysis of Metabolic Reprogramming and IGF-1 Modulation in SCA3 Transgenic Mice
Spinocerebellar ataxia type 3 (SCA3) is a genetic neurodegenerative disease for which a cure is still needed. Growth hormone (GH) therapy has shown positive effects on the exercise behavior of mice with cerebellar atrophy, retains more Purkinje cells, and exhibits less DNA damage after GH intervention. Insulin-like growth factor 1 (IGF-1) is the downstream mediator of GH that participates in signaling and metabolic regulation for cell growth and modulation pathways, including SCA3-affected pathways. However, the underlying therapeutic mechanisms of GH or IGF-1 in SCA3 are not fully understood. In the present study, tissue-specific genome-scale metabolic network models for SCA3 transgenic mice were proposed based on RNA-seq. An integrative transcriptomic and metabolic network analysis of a SCA3 transgenic mouse model revealed that metabolic signaling pathways were activated to compensate for the metabolic remodeling caused by SCA3 genetic modifications. The effect of IGF-1 intervention on the pathology and balance of SCA3 disease was also explored. IGF-1 has been shown to invoke signaling pathways and improve mitochondrial function and glycolysis pathways to restore cellular functions. As one of the downregulated factors in SCA3 transgenic mice, IGF-1 could be a potential biomarker and therapeutic target.
2020-08-24 | Molecular Mechanisms and Future Therapeutics for Spinocerebellar Ataxia Type 31 (SCA31).
Spinocerebellar ataxia type 31 (SCA31) is one of the autosomal-dominant neurodegenerative disorders that shows progressive cerebellar ataxia as a cardinal symptom. This disease is caused by a 2.5- to 3.8-kb-long complex pentanucleotide repeat containing (TGGAA)n, (TAGAA)n, (TAAAA)n, and (TAAAATAGAA)n in an intron of the gene called BEAN1 (brain expressed, associated with Nedd4). By comparing various pentanucleotide repeats in this particular locus among control Japanese and Caucasian populations, it was found that (TGGAA)n was the only sequence segregating with SCA31, strongly suggesting the pathogenicity of (TGGAA)n. The complex repeat also lies in an intron of another gene, TK2 (thymidine kinase 2), which is transcribed in the opposite direction, indicating that the complex repeat is bi-directionally transcribed as noncoding repeats. In SCA31 human brains, (UGGAA)n, the BEAN1 transcript of SCA31 mutation was found to form abnormal RNA structures called RNA foci in cerebellar Purkinje cell nuclei. Subsequent RNA pulldown analysis disclosed that (UGGAA)n binds to RNA-binding proteins TDP-43, FUS, and hnRNP A2/B1. In fact, TDP-43 was found to co-localize with RNA foci in human SCA31 Purkinje cells. To dissect the pathogenesis of (UGGAA)n in SCA31, we generated transgenic fly models of SCA31 by overexpressing SCA31 complex pentanucleotide repeats in Drosophila. We found that the toxicity of (UGGAA)n is length- and expression level-dependent, and it was dampened by co-expressing TDP-43, FUS, and hnRNP A2/B1. Further investigation revealed that TDP-43 ameliorates (UGGAA)n toxicity by directly fixing the abnormal structure of (UGGAA)n. This led us to propose that TDP-43 acts as an RNA chaperone against toxic (UGGAA)n. Further research on the role of RNA-binding proteins as RNA chaperones may provide a novel therapeutic strategy for SCA31.
oligonucleotides
2026-02-23 | Mutant ATXN1 impacts human and mouse microglia and contributes to cognitive, mood, and motor deficits in SCA1 mice.
Microglia, resident immune cells of the brain, are important players in neurodegeneration. While microglial activation is a hallmark of many neurodegenerative diseases, the specific role of microglia intrinsic factors in microglial activation and disease pathogenesis remains unknown. Spinocerebellar ataxia type-1 (SCA1) is an inherited autosomal dominant neurodegenerative disease characterized by severe neuronal loss and early microglial activation in the cerebellum. SCA1 is caused by CAG repeat expansion in the ubiquitously expressed ATAXIN1 (ATXN1) gene. Using human microglia differentiated from SCA1 patient derived iPSCs, we found that mutant ATXN1 is sufficient to alter morphology, gene and protein expression in human microglia in a cell-autonomous manner. Moreover, compared to controls, human SCA1 microglia exhibited increased phagocytosis and pro-inflammatory cytokine production, indicating an immune priming. To determine the extent to which mutant ATXN1 in microglia contributes to SCA1 pathogenesis and behavioral symptoms, we removed mutant ATXN1 from microglia and macrophages in a novel conditional SCA1 mouse model, f-ATXN1146Q/2Q mice. Microglial mutant ATXN1 reduction led to a marked correction in microglia phenotype, in particular in the transcriptomic signature of interferon type 1 mediated immune response, reduced microglial density and resulted in smaller microglia with reduced branching in the cerebellum. Pathology of Purkinje neurons and cerebellar astrogliosis were also ameliorated. Utilizing a battery of behavioral tests, we found that microglia and macrophage mutant ATXN1 reduction ameliorated cognitive, mood, and motor deficits in SCA1 mice. Together, these results indicate that mutant ATXN1 directly impacts microglial phenotype in SCA1, contributing to SCA1 pathology and behavioral deficits.
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.
2024-09-24 | Treatment of neurological pathology and inflammation in Machado-Joseph disease through in vivo self-assembled siRNA.
Machado-Joseph disease, also known as spinocerebellar ataxia type 3 (MJD/SCA3), is a fatal autosomal dominant hereditary ataxia characterized by cerebellar ataxia resulting from the abnormal expansion of CAG repeats in exon 10 of the ATXN3 gene. At present, there is no effective treatment for SCA3. Small interfering RNAs (siRNAs) are emerging as potential therapeutic strategies to target the disease-causing mutant ATXN3 (mATXN3) protein specifically. However, the efficiency of delivery of siRNAs remains a major obstacle for clinical application, particularly in brain disorders. The aim of this study was to develop a synthetic biology strategy to reprogram the host liver as a tissue chassis to induce and deliver in vivo self-assembled siRNAs to target the ATXN3 gene. A synthetic construct directed by a cytomegalovirus promoter was designed to encode a neuron-targeting rabies virus glycoprotein tag and mATXN3-siRNA. After intravenous injection, the synthetic construct was taken up by mouse livers, which were then reprogrammed to enable the self-assembly, production and secretion of small extracellular vesicles encapsulating mATXN3-siRNA. The small extracellular vesicle-encapsulated mATXN3-siRNA was transported through the endogenous circulating system of small extracellular vesicles, crossing the blood-brain barrier and reaching the cerebellar cortex and spinal cerebellar tract, where they silenced the ATXN3 gene. Treatment with the synthetic construct for 8 or 12 weeks led to significant improvements in motor balance ability and reduction of cerebellar atrophy in YACMJD84.2 transgenic mice. The number of Purkinje cells in the cerebellar cortex was significantly increased, and the loss of myelin basic protein was reduced. Moreover, the quantity of neurotoxic nuclear inclusion bodies and the expression of glial fibrillary acidic protein, which promotes neuroinflammation in activated astrocytes, were decreased significantly. The synthetic construct facilitated the generation and delivery of in vivo self-assembled siRNA to the cerebellar cortex and spinal cerebellar tract, thereby inhibiting the expression of mATXN3 protein. This treatment successfully addressed motor impairments, alleviated neuropathological phenotypes and mitigated neuroinflammation in YACMJD84.2 transgenic mice. Our strategy effectively overcomes the primary challenges associated with siRNA therapy for cerebellar ataxia, offering a promising avenue for future clinical treatments.
2023-10-28 | GGC expansion inZFHX3causes SCA4 and impairs autophagy
Abstract Despite linkage to 16q in 1996, the mutation for spinocerebellar ataxia type 4 (SCA4), a late-onset sensory and cerebellar ataxia, escaped detection for 25 years. Using long- read PacBio-HiFi and ONT-Nanopre sequencing and bioinformatic analysis, we identified expansion of a GGC DNA repeat in a >85% GC-rich region in exon 10 of the ZFHX3 gene coding for poly-glycine (polyG). In a total of 15 nuclear families from Utah and 9 from Europe, the repeat was expanded to >40 repeats in SCA4 patients accompanied by significant phenotypic variation independent of repeat size compared to the most common normal repeat size of 21 repeats. The RE event likely occurred in a frequent Swedish haplotype shared by cases from Utah and Germany. Six characteristic ultra-rare SNVs in the vicinity of the RE in cases from Utah and Lübeck (Germany) indicate a common founder event for some of the patients. In fibroblast and iPS cells, the GGC expansion leads to increased ZFHX3 protein levels, polyG aggregates, and abnormal autophagy, which normalized with ZFHX3 siRNA. Increasing autophagic flux may provide a therapeutic avenue for this novel polyG disease.
2023-07-24 | Autosomal dominant cerebellar ataxias: new genes and progress towards treatments.
Dominantly inherited spinocerebellar ataxias (SCAs) are associated with phenotypes that range from pure cerebellar to multisystemic. The list of implicated genes has lengthened in the past 5 years with the inclusion of SCA37/DAB1, SCA45/FAT2, SCA46/PLD3, SCA47/PUM1, SCA48/STUB1, SCA50/NPTX1, SCA25/PNPT1, SCA49/SAM9DL, and SCA27B/FGF14. In some patients, co-occurrence of multiple potentially pathogenic variants can explain variable penetrance or more severe phenotypes. Given this extreme clinical and genetic heterogeneity, genome sequencing should become the diagnostic tool of choice but is still not available in many clinical settings. Treatments tested in phase 2 and phase 3 studies, such as riluzole and transcranial direct current stimulation of the cerebellum and spinal cord, have given conflicting results. To enable early intervention, preataxic carriers of pathogenic variants should be assessed with biomarkers, such as neurofilament light chain and brain MRI; these biomarkers could also be used as outcome measures, given that clinical outcomes are not useful in the preataxic phase. The development of bioassays measuring the concentration of the mutant protein (eg, ataxin-3) might facilitate monitoring of target engagement by gene therapies.
gene therapies
2026-04-30 | Behavioral and Personality Changes as the First Manifestation of Spinocerebellar Ataxia Type 2.
Background. Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the ATXN2 gene. Although classically characterized by progressive cerebellar ataxia and oculomotor abnormalities, increasing evidence indicates that SCA2 is a multisystem disorder with prominent cognitive, behavioral, and psychiatric manifestations. These non-motor symptoms may precede overt motor signs, leading to diagnostic challenges and misdiagnosis as primary psychiatric conditions. Case Presentation. We report the case of a 59-year-old man with a several-year history of progressive behavioral and emotional dysregulation, initially diagnosed as a personality disorder. Prominent features included irritability, impulsivity, disinhibition, hypersexuality, altered eating behavior, and recurrent self-endangering suicidal gestures, with relatively preserved functional autonomy. Neurological examination revealed subtle cerebellar signs. Neuropsychological assessment showed impaired verbal memory with preserved recognition and borderline attentional–executive deficits, consistent with cerebello–frontal dysfunction. Brain magnetic resonance imaging (MRI) demonstrated moderate-to-severe cerebellar and brainstem atrophy, while dopamine transporter SPECT revealed severe bilateral presynaptic dopaminergic denervation. Cerebrospinal fluid biomarkers excluded Alzheimer’s disease. Genetic testing confirmed SCA2 with 38 CAG repeats in ATXN2. Conclusions. This case illustrates an atypical presentation of SCA2 in which behavioral and psychiatric symptoms preceded motor manifestations by several years. Recognition of such presentations is crucial to avoid misdiagnosis, reduce diagnostic delay, and enable timely genetic counselling and multidisciplinary management, reinforcing the concept of SCA2 as a multisystem neurodegenerative disorder.
2026-04-29 | Disease-associated mutations impact DNMT1 function through dynamic allosteric effects and solvent exposure
The inputs and scripts for MD simulations of the WT DNMT1 and its variants associated with autosomal dominant cerebellar ataxia–deafness and neuropathy (ADCA-DN) and hereditary sensory and autonomic neuropathy type 1E (HSAN1E).
2026-03-23 | Hypothalamic Atrophy and Textural Changes in Polyglutamine Ataxias.
Background. Spinocerebellar ataxia (SCA) presents a complex genetic landscape, with over 40 subtypes. These autosomal dominant disorders manifest late onset and severe disability, primarily impacting the cerebellum but also involving other nervous system structures. While a single study has linked hypothalamic atrophy to SCA3, further research is needed to confirm and/or expand this association. This study aimed to investigate hypothalamic involvement in PolyQ SCAs, focusing on SCA 1, 2, 3, and 6. Methods. We studied 135 adult patients with genetically confirmed SCA (SCA1, SCA2, SCA3, and SCA6) and 117 healthy controls. Hypothalamic subregions were segmented using H-SynEx, and both volumetric and texture features were extracted from MR images. Group differences were assessed with the Mann–Whitney U test, and associations with disease duration and severity (measured by SARA) were examined using Spearman’s rank correlation. Results. Significant atrophy of hypothalamic subregions was observed in SCA1, SCA3, and SCA6 when compared with controls, with the anterior subregion being affected in all cases. Texture analysis revealed widespread alterations in SCA1, SCA3, and SCA6 across all subregions. In SCA1 and SCA3, both volumetric and texture measures correlated with disease duration and SARA scores. These findings suggest that hypothalamic involvement in SCAs is complex and may occur before overt clinical manifestations. Key words: Ataxia, Polyglutamine disease, Hypothalamus, MRI, Volumetry
2026-03-15 | Rare but Instructive: Pediatric-Onset Spinocerebellar Ataxia Type 2 and Its Clinical and Genetic Insights.
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the ATXN2 gene. While typically adult-onset, pediatric cases are rare and exhibit distinct clinical features. Here, we report two pediatric-onset SCA2 cases. A 7-year-old boy with involuntary movements, developmental delay, and 58 CAG repeats, and a 16-year-old boy with tremors and gait instability carrying 44 repeats. Both showed cerebellar atrophy on MRI. A literature review of 22 genetically confirmed pediatric SCA2 cases revealed a strong inverse correlation between CAG repeat length and age at onset (R2 = 0.6131, P < 0.00001). Common features included developmental delay, hypotonia, epilepsy, and dystonia, with 79% of cases showing paternal inheritance. These findings underscore the importance of considering SCA2 in children with atypical neurodevelopmental symptoms and highlight the role of genetic anticipation in early-onset cases.
2026-02-17 | Spinocerebellar Ataxia Type 12: From CAG Repeat Expansion to Cortico-Cerebellar Neurodegeneration
Spinocerebellar ataxia type 12 (SCA12) is a rare autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the PPP2R2B gene. Unlike most spinocerebellar ataxias, SCA12 typically begins with a prominent upper limb action tremor, often mimicking essential tremor, and may precede gait ataxia by several years. As the disease progresses, patients develop cerebellar signs, dysarthria, hyperreflexia, and variable cognitive and neuropsychiatric symptoms, including anxiety and depression. Neuroimaging commonly shows cerebellar and cerebral cortical atrophy with relative sparing of brainstem and deep subcortical structures, creating a recognizable radiological pattern. The disorder demonstrates marked phenotypic variability and a strong founder effect in northern India, complicating genotype–phenotype correlations and diagnosis. Emerging evidence suggests that dysregulation of protein phosphatase 2A–related pathways contribute to selective cerebro-cerebellar neurodegeneration. Although no disease-modifying therapy exists, symptomatic treatment of tremor and psychiatric manifestations can substantially improve quality of life. This review integrates clinical, molecular, and neuroimaging evidence to position SCA12 as a distinct CAG repeat disorder characterized by tremor-dominant onset, cortico-cerebellar neurodegeneration, and RNA-mediated toxicity, highlighting the need for biomarker-driven diagnosis and targeted therapeutic development
other
2023-09-07 | DNMT1-associated sensory neuropathy and cerebellar ataxia: A novel variant and review of genotype-phenotype correlation.
Hereditary sensory neuropathy (HSN) 1E is a neurodegenerative disorder caused by pathogenic variants in DNA methyltransferase 1 (DNMT1). It is characterised by sensorineural deafness, sensory neuropathy and cognitive decline. Variants in DNMT1 are also associated with autosomal dominant cerebellar ataxia, deafness and narcolepsy. A 42-year-old man presented with imbalance, lancinating pain, numerous paucisymptomatic injuries, progressive deafness since his mid-20s, mild cognitive decline and apathy. Examination revealed abnormalities of eye movements, distal sensory loss to all modalities, areflexia without weakness and lower limb ataxia. MRI brain and FDG-PET scan demonstrated biparietal and cerebellar atrophy/hypometabolism. Whole exome sequencing detected a heterozygous likely pathogenic missense variant in DNMT1, c.1289G > A, p.Cys430Tyr. Cochlear implant was performed at 44 years for the bilateral high frequency sensorineural hearing loss with improvement in hearing and day-to-day function. We describe a novel variant in DNMT1 and confirm that an overlapping HSN1E-cerebellar phenotype can occur. Only one prior case of cochlear implant in HSN1E has been reported to date but this case adds to that literature, suggesting that cochlear implant can be successful in such patients. We further explore the clinical and radiological signature of the cognitive syndrome associated with this disorder.
2021-06-30 | Generation of induced pluripotent stem cell line (ZZUi0021-A) from a patient with spinocerebellar ataxia type 19.
Spinocerebellar ataxia type 19 (SCA19) is an extremely rare autosomal dominant cerebellar ataxia hereditary that caused by the KCND3 gene mutation. And has a complex pathogenesis. At present, its pathogenesis is still unclear, and there is no effective treatment for SCA19. So, to study its pathogenesis and find effective treatments, we collected the fifibroblasts from a patient with SCA19, then successfully transformed the fifibroblasts into induced pluripotent stem cells (iPSCs) and construct a SCA19 pathological cell mode. This study provides a basis for elucidating its pathogenesis and providing new treatment options.
2021-06-18 | Mesenchymal stem cell-derived exosomes improve motor function and attenuate neuropathology in a mouse model of Machado-Joseph disease.
Machado-Joseph disease is the most common autosomal dominant hereditary ataxia worldwide without effective treatment. Mesenchymal stem cells (MSCs) could slow the disease progression, but side effects limited their clinical application. Besides, MSC-derived exosomes exerted similar efficacy and have many advantages over MSCs. The aim of this study was to examine the efficacy of MSC-derived exosomes in YACMJD84.2 mice. Rotarod performance was evaluated every 2 weeks after a presymptomatic administration of intravenous MSC-derived exosomes twice in YACMJD84.2 mice. Loss of Purkinje cells, relative expression level of Bcl-2/Bax, cerebellar myelin loss, and neuroinflammation were assessed 8 weeks following treatment. MSC-derived exosomes were isolated and purified through anion exchange chromatography. Better coordination in rotarod performance was maintained for 6 weeks in YACMJD84.2 mice with exosomal treatment, compared with those without exosomal treatment. Neuropathological changes including loss of Purkinje cells, cerebellar myelin loss, and neuroinflammation were also attenuated 8 weeks after exosomal treatment. The higher relative ratio of Bcl-2/Bax was consistent with the attenuation of loss of Purkinje cells. MSC-derived exosomes could promote rotarod performance and attenuate neuropathology, including loss of Purkinje cells, cerebellar myelin loss, and neuroinflammation. Therefore, MSC-derived exosomes have a great potential in the treatment of Machado-Joseph disease.
2020-06-02 | Generation of induced pluripotent stem cell line (ZZUi0014-A) from a patient with spinocerebellar ataxia type 3.
Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant disorder that is caused by the abnormal amplification of cytosine-adenine-guanine (CAG) trinucleotide repeats in the ATXN3 gene. The main feature of SCA3 is progressive ataxia. Currently, no effective treatment exists for this condition. For this study, we obtained dermal fibroblasts from a patient. The fibroblasts were successfully transformed into induced pluripotent stem cells (iPSCs) by employing episomal plasmids expressing OCT3/4, SOX2, KLF4, LIN28, and L-MYC. Our approach offers a resource for further research into SCA3 mechanism in an attempt to facilitate the development and screening of pharmaceutical and gene therapy.
2015-05-22 | Human Embryonic Stem Cells in the Treatment of Spinocerebellar Ataxia: A Case Series
Spinocerebellar ataxias, dominantly inherited ataxias, constitute a large heterogenous group of progressive neurodegenerative disorders that commonly affects the cerebellum and its afferent and efferent pathways.No pharmacological treatment has been found to be effective in the treatment of spinocerebellar ataxias.Stem cellbased therapy is emerging as a promising therapeutic option for the treatment of Spinocerebellar ataxias.In this case report, three patients with spinocerebellar ataxias were treated with human embryonic stem cells.Following the treatment, all patient showed noticeable changes in their health such improvement in hand eye coordination, gait pattern, ability to stand without support, muscle strength in all the limbs, ability to walk and turn while standing without support, clearance in speech, good energy levels, reduction in twitching of cheek muscle, stamina, endurance and coordination.
small molecules
2026-09-11 | Spinocerebellar ataxia 27B (FGF14 repeat expansion): Clinical spectrum, diagnostic pitfalls, and implications for late-onset ataxia
Abstract Spinocerebellar ataxia 27B (SCA27B; OMIM 620174) is an autosomal dominant late-onset cerebellar ataxia (LOCA) caused by intronic GAA repeat expansions in FGF14 , first described in 2023. Since its discovery, SCA27B has emerged as a major genetic cause of previously unexplained LOCA across multiple populations. We conducted a narrative review following the Scale for the Assessment of Narrative Review Articles (SANRA) guidance. PubMed, Embase, and Scopus were searched from January 2022 to April 2026 using terms related to SCA27B, FGF14 , GAA repeat expansions, downbeat nystagmus, and aminopyridine therapy. Reference lists of key studies were hand-searched. Human peer-reviewed studies were included, and evidence was synthesized qualitatively by domain. SCA27B typically presents with slowly progressive cerebellar ataxia, prominent downbeat nystagmus, and episodic symptoms such as vertigo, oscillopsia, and transient ataxia that may precede fixed deficits by years. These features are important diagnostic clues in patients otherwise labeled as having idiopathic ataxia or multiple system atrophy of cerebellar type. Prevalence among unsolved LOCA cohorts varies geographically, ranging from 1.2–1.3% in Japan and 1.83% in India to 15–30% in Europe and up to 60% in French-Canadians because of a founder effect. SCA27B is clinically actionable, as many patients experience symptomatic improvement with aminopyridines, particularly 4-aminopyridine. However, evidence remains observational, with no randomized controlled trials available. We review the genetics, epidemiology, clinical spectrum, imaging findings, differential diagnosis, and management of SCA27B, and support routine FGF14 testing in patients with unexplained late-onset ataxia, downbeat nystagmus, or episodic cerebellar symptoms.
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.
2026-05-23 | Rad23b exacerbates pathological aggregates through disrupting proteasome functions in Spinocerebellar ataxia type 3.
Spinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant ataxia globally, caused by expanded CAG repeats in the ATXN3 gene and consequent pathogenic accumulation of mutant ATXN3 (mATXN3) aggregates. The formation of these aggregates perturbs neuronal functions and leads to progressive neurodegeneration, yet the molecular mechanisms controlling mATXN3 proteostasis remain incompletely understood. Here, we identify RAD23 homolog B (Rad23b), a ubiquitin-binding shuttle factor, as a potential regulator of mATXN3 aggregates and toxicity upon high throughput proteomic analysis. Functional assays reveal that Rad23b overexpression enhances, while Rad23b knockdown or knockout reduces, mATXN3 aggregates and neuronal cell death. Mechanistically, Rad23b directly interacts with mATXN3, promotes its ubiquitination, and facilitates its delivery to the proteasome. Paradoxically, Rad23b disrupts proteasome catalytic activity, preventing mATXN3 degradation and exacerbating aggregate formation. Immunohistochemical analysis in SCA3 transgenic mice confirms colocalization of Rad23b with mATXN3 aggregates in cerebellar neurons. These findings highlight Rad23b as a crucial modulator of mATXN3 proteostasis, and imply Rad23b as a potential therapeutic target in SCA3.
2026-05-08 | Role of nuclear transport receptor KPNB1 in the pathophysiology of spinocerebellar ataxia type 3
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is the most common form of autosomal dominant hereditary ataxias and characterized by a pathological expansion of the polyglutamine (polyQ) tract within the ataxin-3 protein. Ataxin- 3 is mainly a cytoplasmic protein, although polyQ-expanded ataxin-3 accumulates in the nucleus of affected neurons and forms intranuclear aggregates, leading to neurotoxicity and cell death. Unravelling the underlying mechanisms in the nuclear localization of polyQ- expanded ataxin-3 and its involvement in neurotoxicity can provide insight into the pathogenesis of this disease and the development of novel therapeutic strategies. In this respect, investigation of the nucleocytoplasmic transport machinery and its implication for the pathogenesis of SCA3 and other polyQ diseases has gathered attention. Our lab has previously indicated the critical importance of karyopherin α-3 (KPNA3), a nuclear transport receptor, in the nuclear transport of ataxin-3 and its implication in the pathogenesis of SCA3. Since KPNA3 functions as an adaptor protein for karyopherin β-1 (KPNB1) in the nuclear transport of protein cargos, we aimed to explore the role of KPNB1 in the pathogenesis of SCA3 as well. Here, we report on SCA3 cell model-based analysis of the nuclear transport receptor KPNB1 and its implications for the pathogenesis of SCA3. We figured out that KPNB1 interacts directly with both wild-type and polyQ-expanded ataxin-3. However, modulating KPNB1 levels did not change the subcellular distribution of ataxin-3. Interestingly, KPNB1 overexpression reduced protein levels and aggregation of ataxin-3 and promoted its cleavage, whereas its knockdown and pharmacological inhibition led to an increase in soluble and insoluble levels of ataxin-3. Our data revealed that modulation of ataxin-3 was apparently based on protein fragmentation, independent of the classical SCA3-associated proteolytic pathways. Label-free quantitative proteomics and knockdown experiments indicated mitochondrial protease CLPP as a potential mediator of the ataxin-3-degrading effect induced by KPNB1 overexpression. We confirmed a reduction of KPNB1 protein levels in SCA3 by analyzing two SCA3 transgenic mouse models and induced pluripotent stem cells (iPSCs) derived from SCA3 patients. Our findings suggested a yet undescribed regulatory function of KPNB1 in modulating ataxin-3, thereby highlighting a new potential target of therapeutic value for SCA3.
2026-03-10 | Computational screening of natural small molecules as dual ATXN3 and LC3 binders for an autophagy-based strategy in spinocerebellar ataxia type 3
Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the ATXN3 gene, producing a polyglutamine expanded ataxin‑3 protein that misfolds, aggregates, and drives progressive neurodegeneration. Enhancing the selective autophagic clearance of mutant ATXN3 through recruitment to the autophagy adaptor LC3 on autophagosomal membranes represents a promising disease-modifying strategy. This study investigates whether natural small molecules can act as dual binders of ATXN3 and LC3, providing accessible scaffolds for an autophagy-based therapeutic approach in SCA3. The Josephin domain of human ATXN3 and human LC3 were prepared as receptor structures. Five natural ligands, quercetin, kaempferol, luteolin, rutin, and trehalose, were subjected to Vina-based molecular docking. For each ligand-target pair, the lowest energy pose was selected and analyzed for predicted binding free energies (ΔG, kcal/mol), hydrogen bond networks, and hydrophobic contacts. Pharmacokinetic properties were evaluated using SwissADME to assess drug likeness and oral bioavailability. Quercetin, kaempferol, and luteolin showed strong and balanced predicted binding to ATXN3 (-8.5 to -8.1 kcal/mol) and LC3 (-8.4 to -8.3 kcal/mol), with molecular weights 286-302 g/mol, high predicted gastrointestinal absorption, and no Lipinski violations. Rutin and trehalose bound ATXN3 weakly (-6.4 and -5.2 kcal/mol, respectively) but displayed strong ending to LC3 (-10.3 and -7.8 kcal/mol), though with poor oral drug-like properties (MW 610.52 and 342.30 g/mol, respectively, low gastrointestinal absorption and multiple Lipinski violations. Common natural flavonoids, particularly quercetin, kaempferol, and luteolin, exhibit strong dual-target binding with favorable oral drug-like properties, supporting their potential as simple scaffolds for autophagy-based therapeutic strategies in SCA3. These findings provide a clear rationale for subsequent biochemical and cellular validation of their ATTEC like mechanisms.
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2025-04-28 | Restoration of Shal/KV4 proteostasis and motor function in a Drosophila model of spinocerebellar ataxia type 19/22.
Loss-of-function mutations in the human KCND3 gene encoding KV4.3 K+ channels are linked to the autosomal dominant neurodegenerative disease spinocerebellar ataxia type 19/22 (SCA19/22). Previous biophysical and biochemical analyses in vitro support the notion that the autosomal dominant inheritance pattern of SCA19/22 is associated with the dominant-negative effects of disease-causing KV4.3 mutants on proteostasis of their wild-type (WT) counterpart. Herein we aimed to explore whether the disease-causing mutants might perturb protein expression of endogenous KV4.3 channel in human cells, as well as contributing to in vivo pathomechanisms underlying motor impairments and neurodegeneration in an animal model of SCA19/22. Substantial reduction in human KV4.3 protein level was validated in skin fibroblasts derived from heterozygous SCA19/22 patients. Genetic knockdown of endogenous Shal, the fly ortholog of human KV4.3, in Drosophila led to locomotor impairment, ommatidia degeneration, and reduced brain cortex thickness, all of which was effectively ameliorated by transgenic expression of human KV4.3, but not KV1.1 K+ channel. Transgenic expression of SCA19/22-causing human KV4.3 mutants resulted in notable disruption of endogenous Shal proteostasis, locomotor function, and ommatidia morphology in Drosophila. Enhanced expression of the Drosophila molecular chaperones HSC70 and HSP83 in our fly model of SCA19/22 corrected Shal protein deficit, locomotor dysfunction, and neurodegeneration. Overexpression of Hsp90β also upregulated endogenous human KV4.3 protein level in patient-derived skin fibroblasts. Our findings highlight Drosophila as a suitable animal model for studying KV4.3 channelopathy in vivo, and accentuate a critical role of defective KV4.3 proteostasis in the pathogenesis of motor dysfunction and neurodegeneration in SCA19/22.
2025-03-27 | Functional characterization of two KCND3 variants associated with SCA 19/22 ataxia in Latin American families.
Spinocerebellar ataxia 19/22 (SCA19/22) represents a rare autosomal dominant genetic disorder resulting in progressive ataxia and cerebellar atrophy. SCA19/22 is caused by variants in the KCND3 gene, which encodes a voltage-gated potassium channel subunit essential for cerebellar Purkinje cell function. To date, 22 variants have been reported worldwide, with incomplete functional studies. We present four Chilean and Mexican cases in whom two single-nucleotide variants were identified through whole-exome sequencing of the probands. One variant (G371R) was initially cataloged as pathogenic and the other (S357W) as likely pathogenic according to the American College of Medical Genetics and Genomics criteria. The pathogenicity of the G371R variation was confirmed by in-silico mutagenesis. Our molecular models, that include electrostatic potential analysis and algorithms to analyze the pore dimensions (HOLE), indicated that the longer side chain of the arginine narrowed the channel's selectivity filter, while the positive charge modified its surface electrostatic potential, presumably preventing potassium flux. Functional characterization of the S357W variant was performed in AD293 cells. When overexpressed, KV4.3S357W channels alone showed no current. Protein electrophoresis revealed that the total number of KV4.3 channels expressed did not differ between the wild-type and mutated phenotypes, suggesting a protein trafficking malfunction. Co-expression of the KChIP2 auxiliary subunit partially rescued the potassium currents when the variant was expressed, albeit with very different biophysical characteristics, including faster inactivation vs. wild-type channels. This functional characterization of two KCND3 variants associated with SCA19/22 adds new evidence for the pathogenic role of Kv4.3 loss-of-function mutations and establishes a correlation between functional dominance and clinical severity in SCA19/22.
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 .
2021-07-26 | Transcriptomic and Metabolic Network Analysis of Metabolic Reprogramming and IGF-1 Modulation in SCA3 Transgenic Mice
Spinocerebellar ataxia type 3 (SCA3) is a genetic neurodegenerative disease for which a cure is still needed. Growth hormone (GH) therapy has shown positive effects on the exercise behavior of mice with cerebellar atrophy, retains more Purkinje cells, and exhibits less DNA damage after GH intervention. Insulin-like growth factor 1 (IGF-1) is the downstream mediator of GH that participates in signaling and metabolic regulation for cell growth and modulation pathways, including SCA3-affected pathways. However, the underlying therapeutic mechanisms of GH or IGF-1 in SCA3 are not fully understood. In the present study, tissue-specific genome-scale metabolic network models for SCA3 transgenic mice were proposed based on RNA-seq. An integrative transcriptomic and metabolic network analysis of a SCA3 transgenic mouse model revealed that metabolic signaling pathways were activated to compensate for the metabolic remodeling caused by SCA3 genetic modifications. The effect of IGF-1 intervention on the pathology and balance of SCA3 disease was also explored. IGF-1 has been shown to invoke signaling pathways and improve mitochondrial function and glycolysis pathways to restore cellular functions. As one of the downregulated factors in SCA3 transgenic mice, IGF-1 could be a potential biomarker and therapeutic target.
2020-08-24 | Molecular Mechanisms and Future Therapeutics for Spinocerebellar Ataxia Type 31 (SCA31).
Spinocerebellar ataxia type 31 (SCA31) is one of the autosomal-dominant neurodegenerative disorders that shows progressive cerebellar ataxia as a cardinal symptom. This disease is caused by a 2.5- to 3.8-kb-long complex pentanucleotide repeat containing (TGGAA)n, (TAGAA)n, (TAAAA)n, and (TAAAATAGAA)n in an intron of the gene called BEAN1 (brain expressed, associated with Nedd4). By comparing various pentanucleotide repeats in this particular locus among control Japanese and Caucasian populations, it was found that (TGGAA)n was the only sequence segregating with SCA31, strongly suggesting the pathogenicity of (TGGAA)n. The complex repeat also lies in an intron of another gene, TK2 (thymidine kinase 2), which is transcribed in the opposite direction, indicating that the complex repeat is bi-directionally transcribed as noncoding repeats. In SCA31 human brains, (UGGAA)n, the BEAN1 transcript of SCA31 mutation was found to form abnormal RNA structures called RNA foci in cerebellar Purkinje cell nuclei. Subsequent RNA pulldown analysis disclosed that (UGGAA)n binds to RNA-binding proteins TDP-43, FUS, and hnRNP A2/B1. In fact, TDP-43 was found to co-localize with RNA foci in human SCA31 Purkinje cells. To dissect the pathogenesis of (UGGAA)n in SCA31, we generated transgenic fly models of SCA31 by overexpressing SCA31 complex pentanucleotide repeats in Drosophila. We found that the toxicity of (UGGAA)n is length- and expression level-dependent, and it was dampened by co-expressing TDP-43, FUS, and hnRNP A2/B1. Further investigation revealed that TDP-43 ameliorates (UGGAA)n toxicity by directly fixing the abnormal structure of (UGGAA)n. This led us to propose that TDP-43 acts as an RNA chaperone against toxic (UGGAA)n. Further research on the role of RNA-binding proteins as RNA chaperones may provide a novel therapeutic strategy for SCA31.
oligonucleotides
2026-02-23 | Mutant ATXN1 impacts human and mouse microglia and contributes to cognitive, mood, and motor deficits in SCA1 mice.
Microglia, resident immune cells of the brain, are important players in neurodegeneration. While microglial activation is a hallmark of many neurodegenerative diseases, the specific role of microglia intrinsic factors in microglial activation and disease pathogenesis remains unknown. Spinocerebellar ataxia type-1 (SCA1) is an inherited autosomal dominant neurodegenerative disease characterized by severe neuronal loss and early microglial activation in the cerebellum. SCA1 is caused by CAG repeat expansion in the ubiquitously expressed ATAXIN1 (ATXN1) gene. Using human microglia differentiated from SCA1 patient derived iPSCs, we found that mutant ATXN1 is sufficient to alter morphology, gene and protein expression in human microglia in a cell-autonomous manner. Moreover, compared to controls, human SCA1 microglia exhibited increased phagocytosis and pro-inflammatory cytokine production, indicating an immune priming. To determine the extent to which mutant ATXN1 in microglia contributes to SCA1 pathogenesis and behavioral symptoms, we removed mutant ATXN1 from microglia and macrophages in a novel conditional SCA1 mouse model, f-ATXN1146Q/2Q mice. Microglial mutant ATXN1 reduction led to a marked correction in microglia phenotype, in particular in the transcriptomic signature of interferon type 1 mediated immune response, reduced microglial density and resulted in smaller microglia with reduced branching in the cerebellum. Pathology of Purkinje neurons and cerebellar astrogliosis were also ameliorated. Utilizing a battery of behavioral tests, we found that microglia and macrophage mutant ATXN1 reduction ameliorated cognitive, mood, and motor deficits in SCA1 mice. Together, these results indicate that mutant ATXN1 directly impacts microglial phenotype in SCA1, contributing to SCA1 pathology and behavioral deficits.
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.
2024-09-24 | Treatment of neurological pathology and inflammation in Machado-Joseph disease through in vivo self-assembled siRNA.
Machado-Joseph disease, also known as spinocerebellar ataxia type 3 (MJD/SCA3), is a fatal autosomal dominant hereditary ataxia characterized by cerebellar ataxia resulting from the abnormal expansion of CAG repeats in exon 10 of the ATXN3 gene. At present, there is no effective treatment for SCA3. Small interfering RNAs (siRNAs) are emerging as potential therapeutic strategies to target the disease-causing mutant ATXN3 (mATXN3) protein specifically. However, the efficiency of delivery of siRNAs remains a major obstacle for clinical application, particularly in brain disorders. The aim of this study was to develop a synthetic biology strategy to reprogram the host liver as a tissue chassis to induce and deliver in vivo self-assembled siRNAs to target the ATXN3 gene. A synthetic construct directed by a cytomegalovirus promoter was designed to encode a neuron-targeting rabies virus glycoprotein tag and mATXN3-siRNA. After intravenous injection, the synthetic construct was taken up by mouse livers, which were then reprogrammed to enable the self-assembly, production and secretion of small extracellular vesicles encapsulating mATXN3-siRNA. The small extracellular vesicle-encapsulated mATXN3-siRNA was transported through the endogenous circulating system of small extracellular vesicles, crossing the blood-brain barrier and reaching the cerebellar cortex and spinal cerebellar tract, where they silenced the ATXN3 gene. Treatment with the synthetic construct for 8 or 12 weeks led to significant improvements in motor balance ability and reduction of cerebellar atrophy in YACMJD84.2 transgenic mice. The number of Purkinje cells in the cerebellar cortex was significantly increased, and the loss of myelin basic protein was reduced. Moreover, the quantity of neurotoxic nuclear inclusion bodies and the expression of glial fibrillary acidic protein, which promotes neuroinflammation in activated astrocytes, were decreased significantly. The synthetic construct facilitated the generation and delivery of in vivo self-assembled siRNA to the cerebellar cortex and spinal cerebellar tract, thereby inhibiting the expression of mATXN3 protein. This treatment successfully addressed motor impairments, alleviated neuropathological phenotypes and mitigated neuroinflammation in YACMJD84.2 transgenic mice. Our strategy effectively overcomes the primary challenges associated with siRNA therapy for cerebellar ataxia, offering a promising avenue for future clinical treatments.
2023-10-28 | GGC expansion inZFHX3causes SCA4 and impairs autophagy
Abstract Despite linkage to 16q in 1996, the mutation for spinocerebellar ataxia type 4 (SCA4), a late-onset sensory and cerebellar ataxia, escaped detection for 25 years. Using long- read PacBio-HiFi and ONT-Nanopre sequencing and bioinformatic analysis, we identified expansion of a GGC DNA repeat in a >85% GC-rich region in exon 10 of the ZFHX3 gene coding for poly-glycine (polyG). In a total of 15 nuclear families from Utah and 9 from Europe, the repeat was expanded to >40 repeats in SCA4 patients accompanied by significant phenotypic variation independent of repeat size compared to the most common normal repeat size of 21 repeats. The RE event likely occurred in a frequent Swedish haplotype shared by cases from Utah and Germany. Six characteristic ultra-rare SNVs in the vicinity of the RE in cases from Utah and Lübeck (Germany) indicate a common founder event for some of the patients. In fibroblast and iPS cells, the GGC expansion leads to increased ZFHX3 protein levels, polyG aggregates, and abnormal autophagy, which normalized with ZFHX3 siRNA. Increasing autophagic flux may provide a therapeutic avenue for this novel polyG disease.
2023-07-24 | Autosomal dominant cerebellar ataxias: new genes and progress towards treatments.
Dominantly inherited spinocerebellar ataxias (SCAs) are associated with phenotypes that range from pure cerebellar to multisystemic. The list of implicated genes has lengthened in the past 5 years with the inclusion of SCA37/DAB1, SCA45/FAT2, SCA46/PLD3, SCA47/PUM1, SCA48/STUB1, SCA50/NPTX1, SCA25/PNPT1, SCA49/SAM9DL, and SCA27B/FGF14. In some patients, co-occurrence of multiple potentially pathogenic variants can explain variable penetrance or more severe phenotypes. Given this extreme clinical and genetic heterogeneity, genome sequencing should become the diagnostic tool of choice but is still not available in many clinical settings. Treatments tested in phase 2 and phase 3 studies, such as riluzole and transcranial direct current stimulation of the cerebellum and spinal cord, have given conflicting results. To enable early intervention, preataxic carriers of pathogenic variants should be assessed with biomarkers, such as neurofilament light chain and brain MRI; these biomarkers could also be used as outcome measures, given that clinical outcomes are not useful in the preataxic phase. The development of bioassays measuring the concentration of the mutant protein (eg, ataxin-3) might facilitate monitoring of target engagement by gene therapies.
gene therapies
2026-04-30 | Behavioral and Personality Changes as the First Manifestation of Spinocerebellar Ataxia Type 2.
Background. Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the ATXN2 gene. Although classically characterized by progressive cerebellar ataxia and oculomotor abnormalities, increasing evidence indicates that SCA2 is a multisystem disorder with prominent cognitive, behavioral, and psychiatric manifestations. These non-motor symptoms may precede overt motor signs, leading to diagnostic challenges and misdiagnosis as primary psychiatric conditions. Case Presentation. We report the case of a 59-year-old man with a several-year history of progressive behavioral and emotional dysregulation, initially diagnosed as a personality disorder. Prominent features included irritability, impulsivity, disinhibition, hypersexuality, altered eating behavior, and recurrent self-endangering suicidal gestures, with relatively preserved functional autonomy. Neurological examination revealed subtle cerebellar signs. Neuropsychological assessment showed impaired verbal memory with preserved recognition and borderline attentional–executive deficits, consistent with cerebello–frontal dysfunction. Brain magnetic resonance imaging (MRI) demonstrated moderate-to-severe cerebellar and brainstem atrophy, while dopamine transporter SPECT revealed severe bilateral presynaptic dopaminergic denervation. Cerebrospinal fluid biomarkers excluded Alzheimer’s disease. Genetic testing confirmed SCA2 with 38 CAG repeats in ATXN2. Conclusions. This case illustrates an atypical presentation of SCA2 in which behavioral and psychiatric symptoms preceded motor manifestations by several years. Recognition of such presentations is crucial to avoid misdiagnosis, reduce diagnostic delay, and enable timely genetic counselling and multidisciplinary management, reinforcing the concept of SCA2 as a multisystem neurodegenerative disorder.
2026-04-29 | Disease-associated mutations impact DNMT1 function through dynamic allosteric effects and solvent exposure
The inputs and scripts for MD simulations of the WT DNMT1 and its variants associated with autosomal dominant cerebellar ataxia–deafness and neuropathy (ADCA-DN) and hereditary sensory and autonomic neuropathy type 1E (HSAN1E).
2026-03-23 | Hypothalamic Atrophy and Textural Changes in Polyglutamine Ataxias.
Background. Spinocerebellar ataxia (SCA) presents a complex genetic landscape, with over 40 subtypes. These autosomal dominant disorders manifest late onset and severe disability, primarily impacting the cerebellum but also involving other nervous system structures. While a single study has linked hypothalamic atrophy to SCA3, further research is needed to confirm and/or expand this association. This study aimed to investigate hypothalamic involvement in PolyQ SCAs, focusing on SCA 1, 2, 3, and 6. Methods. We studied 135 adult patients with genetically confirmed SCA (SCA1, SCA2, SCA3, and SCA6) and 117 healthy controls. Hypothalamic subregions were segmented using H-SynEx, and both volumetric and texture features were extracted from MR images. Group differences were assessed with the Mann–Whitney U test, and associations with disease duration and severity (measured by SARA) were examined using Spearman’s rank correlation. Results. Significant atrophy of hypothalamic subregions was observed in SCA1, SCA3, and SCA6 when compared with controls, with the anterior subregion being affected in all cases. Texture analysis revealed widespread alterations in SCA1, SCA3, and SCA6 across all subregions. In SCA1 and SCA3, both volumetric and texture measures correlated with disease duration and SARA scores. These findings suggest that hypothalamic involvement in SCAs is complex and may occur before overt clinical manifestations. Key words: Ataxia, Polyglutamine disease, Hypothalamus, MRI, Volumetry
2026-03-15 | Rare but Instructive: Pediatric-Onset Spinocerebellar Ataxia Type 2 and Its Clinical and Genetic Insights.
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the ATXN2 gene. While typically adult-onset, pediatric cases are rare and exhibit distinct clinical features. Here, we report two pediatric-onset SCA2 cases. A 7-year-old boy with involuntary movements, developmental delay, and 58 CAG repeats, and a 16-year-old boy with tremors and gait instability carrying 44 repeats. Both showed cerebellar atrophy on MRI. A literature review of 22 genetically confirmed pediatric SCA2 cases revealed a strong inverse correlation between CAG repeat length and age at onset (R2 = 0.6131, P < 0.00001). Common features included developmental delay, hypotonia, epilepsy, and dystonia, with 79% of cases showing paternal inheritance. These findings underscore the importance of considering SCA2 in children with atypical neurodevelopmental symptoms and highlight the role of genetic anticipation in early-onset cases.
2026-02-17 | Spinocerebellar Ataxia Type 12: From CAG Repeat Expansion to Cortico-Cerebellar Neurodegeneration
Spinocerebellar ataxia type 12 (SCA12) is a rare autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the PPP2R2B gene. Unlike most spinocerebellar ataxias, SCA12 typically begins with a prominent upper limb action tremor, often mimicking essential tremor, and may precede gait ataxia by several years. As the disease progresses, patients develop cerebellar signs, dysarthria, hyperreflexia, and variable cognitive and neuropsychiatric symptoms, including anxiety and depression. Neuroimaging commonly shows cerebellar and cerebral cortical atrophy with relative sparing of brainstem and deep subcortical structures, creating a recognizable radiological pattern. The disorder demonstrates marked phenotypic variability and a strong founder effect in northern India, complicating genotype–phenotype correlations and diagnosis. Emerging evidence suggests that dysregulation of protein phosphatase 2A–related pathways contribute to selective cerebro-cerebellar neurodegeneration. Although no disease-modifying therapy exists, symptomatic treatment of tremor and psychiatric manifestations can substantially improve quality of life. This review integrates clinical, molecular, and neuroimaging evidence to position SCA12 as a distinct CAG repeat disorder characterized by tremor-dominant onset, cortico-cerebellar neurodegeneration, and RNA-mediated toxicity, highlighting the need for biomarker-driven diagnosis and targeted therapeutic development
other
2023-09-07 | DNMT1-associated sensory neuropathy and cerebellar ataxia: A novel variant and review of genotype-phenotype correlation.
Hereditary sensory neuropathy (HSN) 1E is a neurodegenerative disorder caused by pathogenic variants in DNA methyltransferase 1 (DNMT1). It is characterised by sensorineural deafness, sensory neuropathy and cognitive decline. Variants in DNMT1 are also associated with autosomal dominant cerebellar ataxia, deafness and narcolepsy. A 42-year-old man presented with imbalance, lancinating pain, numerous paucisymptomatic injuries, progressive deafness since his mid-20s, mild cognitive decline and apathy. Examination revealed abnormalities of eye movements, distal sensory loss to all modalities, areflexia without weakness and lower limb ataxia. MRI brain and FDG-PET scan demonstrated biparietal and cerebellar atrophy/hypometabolism. Whole exome sequencing detected a heterozygous likely pathogenic missense variant in DNMT1, c.1289G > A, p.Cys430Tyr. Cochlear implant was performed at 44 years for the bilateral high frequency sensorineural hearing loss with improvement in hearing and day-to-day function. We describe a novel variant in DNMT1 and confirm that an overlapping HSN1E-cerebellar phenotype can occur. Only one prior case of cochlear implant in HSN1E has been reported to date but this case adds to that literature, suggesting that cochlear implant can be successful in such patients. We further explore the clinical and radiological signature of the cognitive syndrome associated with this disorder.
2021-06-30 | Generation of induced pluripotent stem cell line (ZZUi0021-A) from a patient with spinocerebellar ataxia type 19.
Spinocerebellar ataxia type 19 (SCA19) is an extremely rare autosomal dominant cerebellar ataxia hereditary that caused by the KCND3 gene mutation. And has a complex pathogenesis. At present, its pathogenesis is still unclear, and there is no effective treatment for SCA19. So, to study its pathogenesis and find effective treatments, we collected the fifibroblasts from a patient with SCA19, then successfully transformed the fifibroblasts into induced pluripotent stem cells (iPSCs) and construct a SCA19 pathological cell mode. This study provides a basis for elucidating its pathogenesis and providing new treatment options.
2021-06-18 | Mesenchymal stem cell-derived exosomes improve motor function and attenuate neuropathology in a mouse model of Machado-Joseph disease.
Machado-Joseph disease is the most common autosomal dominant hereditary ataxia worldwide without effective treatment. Mesenchymal stem cells (MSCs) could slow the disease progression, but side effects limited their clinical application. Besides, MSC-derived exosomes exerted similar efficacy and have many advantages over MSCs. The aim of this study was to examine the efficacy of MSC-derived exosomes in YACMJD84.2 mice. Rotarod performance was evaluated every 2 weeks after a presymptomatic administration of intravenous MSC-derived exosomes twice in YACMJD84.2 mice. Loss of Purkinje cells, relative expression level of Bcl-2/Bax, cerebellar myelin loss, and neuroinflammation were assessed 8 weeks following treatment. MSC-derived exosomes were isolated and purified through anion exchange chromatography. Better coordination in rotarod performance was maintained for 6 weeks in YACMJD84.2 mice with exosomal treatment, compared with those without exosomal treatment. Neuropathological changes including loss of Purkinje cells, cerebellar myelin loss, and neuroinflammation were also attenuated 8 weeks after exosomal treatment. The higher relative ratio of Bcl-2/Bax was consistent with the attenuation of loss of Purkinje cells. MSC-derived exosomes could promote rotarod performance and attenuate neuropathology, including loss of Purkinje cells, cerebellar myelin loss, and neuroinflammation. Therefore, MSC-derived exosomes have a great potential in the treatment of Machado-Joseph disease.
2020-06-02 | Generation of induced pluripotent stem cell line (ZZUi0014-A) from a patient with spinocerebellar ataxia type 3.
Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant disorder that is caused by the abnormal amplification of cytosine-adenine-guanine (CAG) trinucleotide repeats in the ATXN3 gene. The main feature of SCA3 is progressive ataxia. Currently, no effective treatment exists for this condition. For this study, we obtained dermal fibroblasts from a patient. The fibroblasts were successfully transformed into induced pluripotent stem cells (iPSCs) by employing episomal plasmids expressing OCT3/4, SOX2, KLF4, LIN28, and L-MYC. Our approach offers a resource for further research into SCA3 mechanism in an attempt to facilitate the development and screening of pharmaceutical and gene therapy.
2015-05-22 | Human Embryonic Stem Cells in the Treatment of Spinocerebellar Ataxia: A Case Series
Spinocerebellar ataxias, dominantly inherited ataxias, constitute a large heterogenous group of progressive neurodegenerative disorders that commonly affects the cerebellum and its afferent and efferent pathways.No pharmacological treatment has been found to be effective in the treatment of spinocerebellar ataxias.Stem cellbased therapy is emerging as a promising therapeutic option for the treatment of Spinocerebellar ataxias.In this case report, three patients with spinocerebellar ataxias were treated with human embryonic stem cells.Following the treatment, all patient showed noticeable changes in their health such improvement in hand eye coordination, gait pattern, ability to stand without support, muscle strength in all the limbs, ability to walk and turn while standing without support, clearance in speech, good energy levels, reduction in twitching of cheek muscle, stamina, endurance and coordination.
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Drug Discovery Landscape
16 orphan drug designations for Autosomal dominant cerebellar ataxia.
16 orphan drug designations for Autosomal dominant cerebellar ataxia.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
4-aminopyridine (4-AP) | small molecules | FDA | — | Solaxa, Inc. |
Befiradol fumarate | small molecules | EMA | — | Neurolixis |
Rovatirelin | small molecules | EMA | 3R Pharma Consulting GmbH | |
Rovatirelin | small molecules | FDA | BioPharma Global, a division of Pace Life Sciences | |
Troriluzole hydrochloride | small molecules | EMA | Biohaven Bioscience Ireland Limited | |
2'-O-methylphosphorothioate RNAoligonucleotide, 5'- m5CUGm5CUGm5CUGm5CUGm5CUGm5CUGm5CUG-3'" | oligonucleotides | FDA | Vico Therapeutics B.V. | |
2'-O-methyl phosphorothioate RNA oligonucleotide, 5'‑m5CUGm5CUGm5CUGm5CUGm5CUGm5CUGm5CUG-3' | oligonucleotides | EMA | Vico Therapeutics B.V. | |
(1E,6E)-1,7-Bis(3,4-dimethoxyphenyl)-4-cyclobutylmethyl-1,6-heptadiene-3,5-dione and [(1E,4Z,6E)-4-(cyclobutylmethyl)-1,7-bis(3,4-dimethoxyphenyl)-5-hydroxyhepta-1,4,6-trien-3-one] | small molecules | FDA | — | AnnJi Pharmaceutical Co. Ltd. |
N-(4,4-difluorocyclohexyl)-2-(3-methyl-1H-pyrazol-1-yl)-6-morpholinopyrimidin-4-amine | small molecules | FDA | — | Novartis Pharmaceuticals Corporation |
Acetylleucine | small molecules | EMA | IntraBio Ireland Ltd | |
N-acetyl-DL-leucine | small molecules | FDA | — | IntraBio Inc. |
Trans-resveratrol | small molecules | EMA | — | Luis Pereira de Almeida |
2-amino-N-({methyl-[(6-trifluoromethoxy-benzothiazol-2-ylcarbamoyl)-methyl]-carbamoyl}-methyl)-acetamide monohydrochloride | small molecules | FDA | Biohaven Pharmaceuticals, Inc. | |
riluzole | small molecules | FDA | Biohaven Pharmaceutical Holding Company, Ltd. | |
Trehalose | small molecules | EMA | FGK Representative Service GmbH | |
Ceftriaxone | small molecules | EMA | — | Ospedale San Raffaele s.r.l. |
“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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