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

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 vulnerabil...

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Published in:Human molecular genetics 2020-11, Vol.29 (19), p.3249-3265
Main Authors: Chopra, Ravi, Bushart, David D, Cooper, John P, Yellajoshyula, Dhananjay, Morrison, Logan M, Huang, Haoran, Handler, Hillary P, Man, Luke J, Dansithong, Warunee, Scoles, Daniel R, Pulst, Stefan M, Orr, Harry T, Shakkottai, Vikram G
Format: Article
Language:English
Subjects:
Animals
Ataxin-1 - genetics
Ataxin-1 - metabolism
Female
Gene Knock-In Techniques
Humans
Ion Channel Gating
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neurons - metabolism
Neurons - pathology
Purkinje Cells - metabolism
Purkinje Cells - pathology
Repressor Proteins - genetics
Repressor Proteins - metabolism
Spinocerebellar Ataxias - genetics
Spinocerebellar Ataxias - metabolism
Spinocerebellar Ataxias - pathology
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Summary: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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddaa212