Mutant ataxin1 disrupts cerebellar development in spinocerebellar ataxia type 1

Chandrakanth Reddy Edamakanti, Jeehaeh Do, Alessandro Didonna, Marco Martina, Puneet Opal*

*Corresponding author for this work

Research output: Contribution to journalArticle

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Abstract

Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the protein ATXN1, which is involved in transcriptional regulation. Although symptoms appear relatively late in life, primarily from cerebellar dysfunction, pathogenesis begins early, with transcriptional changes detectable as early as a week after birth in SCA1-knockin mice. Given the importance of this postnatal period for cerebellar development, we asked whether this region might be developmentally altered by mutant ATXN1. We found that expanded ATXN1 stimulates the proliferation of postnatal cerebellar stem cells in SCA1 mice. These hyperproliferating stem cells tended to differentiate into GABAergic inhibitory interneurons rather than astrocytes; this significantly increased the GABAergic inhibitory interneuron synaptic connections, disrupting cerebellar Purkinje cell function in a non-cell autonomous manner. We confirmed the increased basket cell-Purkinje cell connectivity in human SCA1 patients. Mutant ATXN1 thus alters the neural circuitry of the developing cerebellum, setting the stage for the later vulnerability of Purkinje cells to SCA1. We propose that other late-onset degenerative diseases may also be rooted in subtle developmental derailments.

Original languageEnglish (US)
Pages (from-to)2252-2265
Number of pages14
JournalJournal of Clinical Investigation
Volume128
Issue number6
DOIs
StatePublished - Jun 1 2018

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ASJC Scopus subject areas

  • Medicine(all)

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