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

Summary 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.