Dysregulation of zebrin-II cell subtypes in the cerebellum is a shared feature across polyglutamine ataxia mouse models and patients.

Autor: Bartelt LC; University Program in Genetics & Genomics, Duke University Medical Center, Durham, NC 27710, USA.; Departments of Pathology & Laboratory Medicine, Neurology, Biological Chemistry, and Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92697, USA.; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA., Switonski PM; Department of Neuronal Cell Biology, Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61-704 Poznan, Poland., Adamek G; Department of Neuronal Cell Biology, Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61-704 Poznan, Poland., Longo F; Departments of Pathology & Laboratory Medicine, Neurology, Biological Chemistry, and Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92697, USA., Carvalho J; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA., Duvick LA; Institute for Translational Neuroscience, and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA., Jarrah SI; Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA., McLoughlin HS; Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA., Scoles DR; Department of Neurology, University of Utah, Salt Lake City, UT 84132, USA., Pulst SM; Department of Neurology, University of Utah, Salt Lake City, UT 84132, USA., Orr HT; Institute for Translational Neuroscience, and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA., Hull C; Department of Neurobiology, Duke University School of Medicine, Durham, NC 27710, USA., Lowe CB; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA., La Spada AR; Departments of Pathology & Laboratory Medicine, Neurology, Biological Chemistry, and Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92697, USA.; Department of Neurology, Duke University School of Medicine, Durham, NC 27710, USA.; UCI Center for Neurotherapeutics, University of California, Irvine, Irvine, CA 92697, USA.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2024 Nov 06; Vol. 16 (772), pp. eadn5449. Date of Electronic Publication: 2024 Nov 06.
DOI: 10.1126/scitranslmed.adn5449
Abstrakt: Spinocerebellar ataxia type 7 (SCA7) is a genetic neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. Purkinje cells (PCs) are central to the pathology of ataxias, but their low abundance in the cerebellum underrepresents their transcriptomes in sequencing assays. To address this issue, we developed a PC enrichment protocol and sequenced individual nuclei from mice and patients with SCA7. Single-nucleus RNA sequencing in SCA7-266Q mice revealed dysregulation of cell identity genes affecting glia and PCs. Specifically, genes marking zebrin-II PC subtypes accounted for the highest proportion of DEGs in symptomatic SCA7-266Q mice. These transcriptomic changes in SCA7-266Q mice were associated with increased numbers of inhibitory synapses as quantified by immunohistochemistry and reduced spiking of PCs in acute brain slices. Dysregulation of zebrin-II cell subtypes was the predominant signal in PCs of SCA7-266Q mice and was associated with the loss of zebrin-II striping in the cerebellum at motor symptom onset. We furthermore demonstrated zebrin-II stripe degradation in additional mouse models of polyglutamine ataxia and observed decreased zebrin-II expression in the cerebella of patients with SCA7. Our results suggest that a breakdown of zebrin subtype regulation is a shared pathological feature of polyglutamine ataxias.
Databáze: MEDLINE