Cargando…

Purkinje-Enriched snRNA-seq in SCA7 Cerebellum Reveals Zebrin Identity Loss as a Central Feature of Polyglutamine Ataxias

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. SCA7 patients display a striking loss of Purkinje cell (PC) neurons with disease progression; however, PCs are rare, making them difficult to characterize. We developed a P...

Descripción completa

Detalles Bibliográficos
Autores principales: Bartelt, Luke C., Switonski, Pawel M., Adamek, Grażyna, Carvalho, Juliana, Duvick, Lisa A., Jarrah, Sabrina I., McLoughlin, Hayley S., Scoles, Daniel R., Pulst, Stefan M., Orr, Harry T., Hull, Court, Lowe, Craig B., La Spada, Albert R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10197555/
https://www.ncbi.nlm.nih.gov/pubmed/37214832
http://dx.doi.org/10.1101/2023.03.19.533345
_version_ 1785044575205720064
author Bartelt, Luke C.
Switonski, Pawel M.
Adamek, Grażyna
Carvalho, Juliana
Duvick, Lisa A.
Jarrah, Sabrina I.
McLoughlin, Hayley S.
Scoles, Daniel R.
Pulst, Stefan M.
Orr, Harry T.
Hull, Court
Lowe, Craig B.
La Spada, Albert R.
author_facet Bartelt, Luke C.
Switonski, Pawel M.
Adamek, Grażyna
Carvalho, Juliana
Duvick, Lisa A.
Jarrah, Sabrina I.
McLoughlin, Hayley S.
Scoles, Daniel R.
Pulst, Stefan M.
Orr, Harry T.
Hull, Court
Lowe, Craig B.
La Spada, Albert R.
author_sort Bartelt, Luke C.
collection PubMed
description Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. SCA7 patients display a striking loss of Purkinje cell (PC) neurons with disease progression; however, PCs are rare, making them difficult to characterize. We developed a PC nuclei enrichment protocol and applied it to single-nucleus RNA-seq of a SCA7 knock-in mouse model. Our results unify prior observations into a central mechanism of cell identity loss, impacting both glia and PCs, driving accumulation of inhibitory synapses and altered PC spiking. Zebrin-II subtype dysregulation is the predominant signal in PCs, leading to complete loss of zebrin-II striping at motor symptom onset in SCA7 mice. We show this zebrin-II subtype degradation is shared across Polyglutamine Ataxia mouse models and SCA7 patients. It has been speculated that PC subtype organization is critical for cerebellar function, and our results suggest that a breakdown of zebrin-II parasagittal striping is pathological.
format Online
Article
Text
id pubmed-10197555
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Cold Spring Harbor Laboratory
record_format MEDLINE/PubMed
spelling pubmed-101975552023-05-20 Purkinje-Enriched snRNA-seq in SCA7 Cerebellum Reveals Zebrin Identity Loss as a Central Feature of Polyglutamine Ataxias Bartelt, Luke C. Switonski, Pawel M. Adamek, Grażyna Carvalho, Juliana Duvick, Lisa A. Jarrah, Sabrina I. McLoughlin, Hayley S. Scoles, Daniel R. Pulst, Stefan M. Orr, Harry T. Hull, Court Lowe, Craig B. La Spada, Albert R. bioRxiv Article Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. SCA7 patients display a striking loss of Purkinje cell (PC) neurons with disease progression; however, PCs are rare, making them difficult to characterize. We developed a PC nuclei enrichment protocol and applied it to single-nucleus RNA-seq of a SCA7 knock-in mouse model. Our results unify prior observations into a central mechanism of cell identity loss, impacting both glia and PCs, driving accumulation of inhibitory synapses and altered PC spiking. Zebrin-II subtype dysregulation is the predominant signal in PCs, leading to complete loss of zebrin-II striping at motor symptom onset in SCA7 mice. We show this zebrin-II subtype degradation is shared across Polyglutamine Ataxia mouse models and SCA7 patients. It has been speculated that PC subtype organization is critical for cerebellar function, and our results suggest that a breakdown of zebrin-II parasagittal striping is pathological. Cold Spring Harbor Laboratory 2023-05-11 /pmc/articles/PMC10197555/ /pubmed/37214832 http://dx.doi.org/10.1101/2023.03.19.533345 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Bartelt, Luke C.
Switonski, Pawel M.
Adamek, Grażyna
Carvalho, Juliana
Duvick, Lisa A.
Jarrah, Sabrina I.
McLoughlin, Hayley S.
Scoles, Daniel R.
Pulst, Stefan M.
Orr, Harry T.
Hull, Court
Lowe, Craig B.
La Spada, Albert R.
Purkinje-Enriched snRNA-seq in SCA7 Cerebellum Reveals Zebrin Identity Loss as a Central Feature of Polyglutamine Ataxias
title Purkinje-Enriched snRNA-seq in SCA7 Cerebellum Reveals Zebrin Identity Loss as a Central Feature of Polyglutamine Ataxias
title_full Purkinje-Enriched snRNA-seq in SCA7 Cerebellum Reveals Zebrin Identity Loss as a Central Feature of Polyglutamine Ataxias
title_fullStr Purkinje-Enriched snRNA-seq in SCA7 Cerebellum Reveals Zebrin Identity Loss as a Central Feature of Polyglutamine Ataxias
title_full_unstemmed Purkinje-Enriched snRNA-seq in SCA7 Cerebellum Reveals Zebrin Identity Loss as a Central Feature of Polyglutamine Ataxias
title_short Purkinje-Enriched snRNA-seq in SCA7 Cerebellum Reveals Zebrin Identity Loss as a Central Feature of Polyglutamine Ataxias
title_sort purkinje-enriched snrna-seq in sca7 cerebellum reveals zebrin identity loss as a central feature of polyglutamine ataxias
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10197555/
https://www.ncbi.nlm.nih.gov/pubmed/37214832
http://dx.doi.org/10.1101/2023.03.19.533345
work_keys_str_mv AT barteltlukec purkinjeenrichedsnrnaseqinsca7cerebellumrevealszebrinidentitylossasacentralfeatureofpolyglutamineataxias
AT switonskipawelm purkinjeenrichedsnrnaseqinsca7cerebellumrevealszebrinidentitylossasacentralfeatureofpolyglutamineataxias
AT adamekgrazyna purkinjeenrichedsnrnaseqinsca7cerebellumrevealszebrinidentitylossasacentralfeatureofpolyglutamineataxias
AT carvalhojuliana purkinjeenrichedsnrnaseqinsca7cerebellumrevealszebrinidentitylossasacentralfeatureofpolyglutamineataxias
AT duvicklisaa purkinjeenrichedsnrnaseqinsca7cerebellumrevealszebrinidentitylossasacentralfeatureofpolyglutamineataxias
AT jarrahsabrinai purkinjeenrichedsnrnaseqinsca7cerebellumrevealszebrinidentitylossasacentralfeatureofpolyglutamineataxias
AT mcloughlinhayleys purkinjeenrichedsnrnaseqinsca7cerebellumrevealszebrinidentitylossasacentralfeatureofpolyglutamineataxias
AT scolesdanielr purkinjeenrichedsnrnaseqinsca7cerebellumrevealszebrinidentitylossasacentralfeatureofpolyglutamineataxias
AT pulststefanm purkinjeenrichedsnrnaseqinsca7cerebellumrevealszebrinidentitylossasacentralfeatureofpolyglutamineataxias
AT orrharryt purkinjeenrichedsnrnaseqinsca7cerebellumrevealszebrinidentitylossasacentralfeatureofpolyglutamineataxias
AT hullcourt purkinjeenrichedsnrnaseqinsca7cerebellumrevealszebrinidentitylossasacentralfeatureofpolyglutamineataxias
AT lowecraigb purkinjeenrichedsnrnaseqinsca7cerebellumrevealszebrinidentitylossasacentralfeatureofpolyglutamineataxias
AT laspadaalbertr purkinjeenrichedsnrnaseqinsca7cerebellumrevealszebrinidentitylossasacentralfeatureofpolyglutamineataxias