ArticleHuman molecular genetics2017
Comparison of spinocerebellar ataxia type 3 mouse models identifies early gain-of-function, cell-autonomous transcriptional changes in oligodendrocytes.
Article in Human molecular genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 54 citations in OpenAlex.
- Article
- Oligodendrocyte dysfunction contributes to motor deficits and Purkinje cell axonopathy in spinocerebellar ataxia type 1.The Journal of clinical investigation · 2026Article
- Modulation of the Stress Granule Component Carhsp1 Mitigates Disease-Associated Deficits in Spinocerebellar Ataxia Type 3 Mouse Models.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- IGFBP1 as a metabolic-neurodegenerative biomarker in spinocerebellar ataxia type 3.Experimental and therapeutic medicine · 2026Article
- Experimental Models to Study Polyglutamine Spinocerebellar Ataxias: From Mechanisms to Therapeutic Developments.Cerebellum (London, England) · 2026Review
- Gene editing for Spinocerebellar ataxia type 3 taking advantage of the human ATXN3L paralog as replacement gene.Gene therapy · 2025Article
- Cerebellar lipid dysregulation in SCA3: A comparative study in patients and mice.Neurobiology of disease · 2025Article
- Early transcriptomic perturbations highlight the spinal cord as a key pathogenic region in spinocerebellar ataxia type 3.Frontiers in cellular neuroscience · 2025Article
- Longitudinal single-cell transcriptional dynamics throughout neurodegeneration in SCA1.Neuron · 2024Article
- Widespread alternative splicing dysregulation occurs presymptomatically in CAG expansion spinocerebellar ataxias.Brain : a journal of neurology · 2024Article
- Slc9a6 mutation causes Purkinje cell loss and ataxia in the shaker rat.Human molecular genetics · 2023Article
- Clinically Meaningful Magnetic Resonance Endpoints Sensitive to Preataxic Spinocerebellar Ataxia Types 1 and 3.Annals of neurology · 2023Article
- Myelinating Glia: Potential Therapeutic Targets in Polyglutamine Spinocerebellar Ataxias.Cells · 2023Review
- Disease-associated oligodendrocyte signatures are spatiotemporally dysregulated in spinocerebellar ataxia type 3.Frontiers in neuroscience · 2023Article
- Article
- The extra-cerebellar effects of spinocerebellar ataxia type 1 (SCA1): looking beyond the cerebellum.Cellular and molecular life sciences : CMLS · 2022Review
- Consensus Paper: Strengths and Weaknesses of Animal Models of Spinocerebellar Ataxias and Their Clinical Implications.Cerebellum (London, England) · 2022Article
- Cerebellar morphometric and spectroscopic biomarkers for Machado-Joseph Disease.Acta neuropathologica communications · 2022Article
- Impaired Oligodendrocyte Maturation Is an Early Feature in SCA3 Disease Pathogenesis.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2022Article
- Glutamatergic Synapse Dysfunction inFrontiers in molecular neuroscience · 2022Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by a polyglutamine-encoding CAG repeat expansion in the ATXN3 gene. This expansion leads to misfolding and aggregation of mutant ataxin-3 (ATXN3) and degeneration of select brain regions. A key unanswered question in SCA3 and other polyglutamine diseases is the extent to which neurodegeneration is mediated through gain-of-function versus loss-of-function. To address this question in SCA3, we performed transcriptional profiling on the brainstem, a highly vulnerable brain region in SCA3, in a series of mouse models with varying degrees of ATXN3 expression and aggregation. We include two SCA3 knock-in mouse models: our previously published model that erroneously harbors a tandem duplicate of the CAG repeat-containing exon, and a corrected model, introduced here. Both models exhibit dose-dependent neuronal accumulation and aggregation of mutant ATXN3, but do not exhibit a behavioral phenotype. We identified a molecular signature that correlates with ATXN3 neuronal aggregation yet is primarily linked to oligodendrocytes, highlighting early white matter dysfunction in SCA3. Two robustly elevated oligodendrocyte transcripts, Acy3 and Tnfrsf13c, were confirmed as elevated at the protein level in SCA3 human disease brainstem. To determine if mutant ATXN3 acts on oligodendrocytes cell-autonomously, we manipulated the repeat expansion in the variant SCA3 knock-in mouse by cell-type specific Cre/LoxP recombination. Changes in oligodendrocyte transcripts are driven cell-autonomously and occur independent of neuronal ATXN3 aggregation. Our findings support a primary toxic gain of function mechanism and highlight a previously unrecognized role for oligodendrocyte dysfunction in SCA3 disease pathogenesis.
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