RORα-Mediated Purkinje Cell Development Determines Disease Severity in Adult SCA1 Mice

Heliane G. Serra, Lisa Duvick, Tao Zu, Kerri Carlson, Sam Stevens, Nathan Jorgensen, Alana Lysholm, Eric Burright, Huda Y. Zoghbi, H. Brent Clark, J. Michael Andresen, Harry T. Orr

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199 Scopus citations

Abstract

Spinocerebellar ataxia type 1 (SCA1) is one of nine inherited, typically adult onset, polyglutamine neurodegenerative diseases. To examine whether development impacts SCA1, we used a conditional transgenic mouse model of SCA1 to delay the postnatal expression of mutant ATXN1 until after completion of cerebellar development. Delayed postnatal expression of mutant ATXN1 led to a substantial reduction in severity of disease in adults in comparison with early postnatal gene expression. This was linked to a destabilization of RORα, a transcription factor critical for cerebellar development. In SCA1 mice, there was a depletion of RORα and a reduction in expression of genes controlled by RORα. Partial loss of RORα enhanced mutant ATXN1 pathogenicity. Additionally, evidence points to the existence of a complex containing ATXN1, RORα, and the RORα coactivator Tip60. These studies indicate RORα and Tip60 have a role in SCA1 and suggest a mechanism by which compromising cerebellar development contributes to severity of neurodegeneration in an adult.

Original languageEnglish (US)
Pages (from-to)697-708
Number of pages12
JournalCell
Volume127
Issue number4
DOIs
StatePublished - Nov 17 2006

Bibliographical note

Funding Information:
We appreciate the efforts of R. Ehlenfeldt for handling the mouse colony, J. Sedgewick in the Biomedical Image Processing Lab for assistance with quantitative immunofluorescence, and the Minnesota Super Computer Institute for assistance with microarray data analyses. This work was supported by grants NS22920 and NS45667 to H.T.O. and NS27699 to H.Y.Z. from NIH.

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