ArticleJCI insight2021
Modulation of ATXN1 S776 phosphorylation reveals the importance of allele-specific targeting in SCA1.
Article in JCI insight, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 18 citations in OpenAlex.
- Oligodendrocyte dysfunction contributes to motor deficits and Purkinje cell axonopathy in spinocerebellar ataxia type 1.The Journal of clinical investigation · 2026Article
- Translational Relevance of SCA1 Models for the Development of Therapies for Spinocerebellar Ataxia Type 1.Biomedicines · 2025Review
- Rapid Microwave Fixation of the Brain Reveals Seasonal Changes in the Phosphoproteome of Hibernating Thirteen-Lined Ground Squirrels.ACS chemical neuroscience · 2025Article
- Elevated SLC7A2 expression is associated with an abnormal neuroinflammatory response and nitrosative stress in Huntington's disease.Journal of neuroinflammation · 2024Article
- Molecular Determinants of Neurocognitive Deficits in Glioma: Based on 2021 WHO Classification.Journal of molecular neuroscience : MN · 2024Article
- Widespread alternative splicing dysregulation occurs presymptomatically in CAG expansion spinocerebellar ataxias.Brain : a journal of neurology · 2024Article
- Therapeutic Strategies for Spinocerebellar Ataxia Type 1.Biomolecules · 2023Review
- Alterations in oligodendrocyte transcriptional networks reveal region-specific vulnerabilities to neurological disease.iScience · 2023Article
- Article
- Review
- The extra-cerebellar effects of spinocerebellar ataxia type 1 (SCA1): looking beyond the cerebellum.Cellular and molecular life sciences : CMLS · 2022Review
- Cross-species genetic screens identify transglutaminase 5 as a regulator of polyglutamine-expanded ataxin-1.The Journal of clinical investigation · 2022Article
- Reduction of mutant ATXN1 rescues premature death in a conditional SCA1 mouse model.JCI insight · 2022Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disorder characterized by motor incoordination, mild cognitive decline, respiratory dysfunction, and early lethality. It is caused by the expansion of the polyglutamine (polyQ) tract in Ataxin-1 (ATXN1), which stabilizes the protein, leading to its toxic accumulation in neurons. Previously, we showed that serine 776 (S776) phosphorylation is critical for ATXN1 stability and contributes to its toxicity in cerebellar Purkinje cells. Still, the therapeutic potential of disrupting S776 phosphorylation on noncerebellar SCA1 phenotypes remains unstudied. Here, we report that abolishing S776 phosphorylation specifically on the polyQ-expanded ATXN1 of SCA1-knockin mice reduces ATXN1 throughout the brain and not only rescues the cerebellar motor incoordination but also improves respiratory function and extends survival while not affecting the hippocampal learning and memory deficits. As therapeutic approaches are likely to decrease S776 phosphorylation on polyQ-expanded and WT ATXN1, we further disrupted S776 phosphorylation on both alleles and observed an attenuated rescue, demonstrating a potential protective role of WT allele. This study not only highlights the role of S776 phosphorylation to regulate ATXN1 levels throughout the brain but also suggests distinct brain region-specific disease mechanisms and demonstrates the importance of developing allele-specific therapies for maximal benefits in SCA1.
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