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ResearchIn-Press PreviewGeneticsNeuroscience Open Access | 10.1172/JCI195723

Oligodendrocyte dysfunction contributes to motor deficits and Purkinje cell axonopathy in spinocerebellar ataxia type 1

Changwoo Lee,1 Rosalie M. Grijalva,1 Leon Tejwani,1 Eunwoo Bae,2 Alison Chase,1 Hannah Ro,3 Hannah Kim,3 Victor Olmos,2 James P. Orengo,4 and Janghoo Lim1

1Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, United States of America

2Department of Genetics, Yale School of Medicine, New Haven, United States of America

3Department of Neuroscience, Yale College, New Haven, United States of America

4Departments of Neurology and Neuroscience, Baylor College of Medicine, Houston, United States of America

Find articles by Lee, C. in: PubMed | Google Scholar

1Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, United States of America

2Department of Genetics, Yale School of Medicine, New Haven, United States of America

3Department of Neuroscience, Yale College, New Haven, United States of America

4Departments of Neurology and Neuroscience, Baylor College of Medicine, Houston, United States of America

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1Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, United States of America

2Department of Genetics, Yale School of Medicine, New Haven, United States of America

3Department of Neuroscience, Yale College, New Haven, United States of America

4Departments of Neurology and Neuroscience, Baylor College of Medicine, Houston, United States of America

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1Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, United States of America

2Department of Genetics, Yale School of Medicine, New Haven, United States of America

3Department of Neuroscience, Yale College, New Haven, United States of America

4Departments of Neurology and Neuroscience, Baylor College of Medicine, Houston, United States of America

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1Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, United States of America

2Department of Genetics, Yale School of Medicine, New Haven, United States of America

3Department of Neuroscience, Yale College, New Haven, United States of America

4Departments of Neurology and Neuroscience, Baylor College of Medicine, Houston, United States of America

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1Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, United States of America

2Department of Genetics, Yale School of Medicine, New Haven, United States of America

3Department of Neuroscience, Yale College, New Haven, United States of America

4Departments of Neurology and Neuroscience, Baylor College of Medicine, Houston, United States of America

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1Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, United States of America

2Department of Genetics, Yale School of Medicine, New Haven, United States of America

3Department of Neuroscience, Yale College, New Haven, United States of America

4Departments of Neurology and Neuroscience, Baylor College of Medicine, Houston, United States of America

Find articles by Kim, H. in: PubMed | Google Scholar

1Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, United States of America

2Department of Genetics, Yale School of Medicine, New Haven, United States of America

3Department of Neuroscience, Yale College, New Haven, United States of America

4Departments of Neurology and Neuroscience, Baylor College of Medicine, Houston, United States of America

Find articles by Olmos, V. in: PubMed | Google Scholar

1Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, United States of America

2Department of Genetics, Yale School of Medicine, New Haven, United States of America

3Department of Neuroscience, Yale College, New Haven, United States of America

4Departments of Neurology and Neuroscience, Baylor College of Medicine, Houston, United States of America

Find articles by Orengo, J. in: PubMed | Google Scholar |

1Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, United States of America

2Department of Genetics, Yale School of Medicine, New Haven, United States of America

3Department of Neuroscience, Yale College, New Haven, United States of America

4Departments of Neurology and Neuroscience, Baylor College of Medicine, Houston, United States of America

Find articles by Lim, J. in: PubMed | Google Scholar |

Published May 11, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI195723.
Copyright © 2026, Lee et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 11, 2026 - Version history
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Abstract

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease marked by progressive motor deficits and Purkinje cell (PC) degeneration, driven by polyglutamine expansion in ataxin-1. While oligodendroglial dysfunction precedes PC loss, its direct contribution toward SCA1 pathogenesis remains unclear. Here, using an oligodendroglia-specific SCA1 conditional knock-in mouse model, we demonstrate that mutant ataxin-1 in oligodendrocytes is sufficient to drive aspects of SCA1-related pathology, including dysregulated myelination, PC axonal shrinkage, and torpedo formation, ultimately impairing motor coordination. Transcriptomic analysis uncovers cerebellar oligodendrocyte subtypes with distinct gene expression signatures and aberrant abundance that contribute to demyelination. This, compounded by a progressive decline in the neuroprotective functions of a cerebellar-specific oligodendrocyte subtype, establishes a critical link between demyelination, axo-myelinic dysfunction, and axonal pathology in SCA1. Upstream transcriptional regulator analysis in oligodendroglia identifies TCF7L2 and HTT as key mediators of oligodendroglial dysfunction in SCA1, suggesting shared pathogenic mechanisms with other polyglutamine diseases. Collectively, these findings establish oligodendroglia as key mediators of SCA1 pathogenesis and underscore their critical role in preserving PC axonal integrity.

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  • Version 1 (May 11, 2026): In-Press Preview
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