Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in spinocerebellar ataxia type 1

Ravi Chopra, David D. Bushart, John P. Cooper, Dhananjay Yellajoshyula, Logan M. Morrison, Haoran Huang, Hillary P. Handler, Luke J. Man, Warunee Dansithong, Daniel R. Scoles, Stefan M. Pulst, Harry T. Orr, Vikram G. Shakkottai

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Selective neuronal vulnerability in neurodegenerative disease is poorly understood. Using the ATXN1[82Q] model of spinocerebellar ataxia type 1 (SCA1), we explored the hypothesis that regional differences in Purkinje neuron degeneration could provide novel insights into selective vulnerability. ATXN1[82Q] Purkinje neurons from the anterior cerebellum were found to degenerate earlier than those from the nodular zone, and this early degeneration was associated with selective dysregulation of ion channel transcripts and altered Purkinje neuron spiking. Efforts to understand the basis for selective dysregulation of channel transcripts revealed modestly increased expression of the ATXN1 co-repressor Capicua (Cic) in anterior cerebellar Purkinje neurons. Importantly, disrupting the association between ATXN1 and Cic rescued the levels of these ion channel transcripts, and lentiviral overexpression of Cic in the nodular zone accelerated both aberrant Purkinje neuron spiking and neurodegeneration. These findings reinforce the central role for Cic in SCA1 cerebellar pathophysiology and suggest that only modest reductions in Cic are needed to have profound therapeutic impact in SCA1.

Original languageEnglish (US)
Pages (from-to)3249-3265
Number of pages17
JournalHuman molecular genetics
Volume29
Issue number19
DOIs
StatePublished - Oct 1 2020

Bibliographical note

Funding Information:
National Institutes of Health (R01 NS085054 to V.G.S., R01 NS022920 to H.T.O., R37NS033123 to S.M.P., R01NS097903 to S.M.P., U01NS103883 to D.R.S. and S.M.P., T32GM007863 to R.C.); National Ataxia Foundation Research Post-Doctoral Fellowship Award (R.C.).

Publisher Copyright:
© 2020 The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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