Abstract
Spinocerebellar ataxia type 1 (SCA1) is one of nine dominantly inherited neurodegenerative diseases caused by polyglutamine tract expansion. In SCA1, the expanded polyglutamine tract is in the ataxin-1 (ATXN1) protein. ATXN1 is part of an in vivo complex with retinoid acid receptor-related orphan receptor alpha (Rora) and the acetyltransferase tat-interactive protein 60 kDa (Tip60). ATXN1 and Tip60 interact directly via the ATXN1 and HMG-box protein 1 (AXH) domain of ATXN1. Moreover, the phospho-mimicking Asp amino acid at position 776, previously shown to enhance pathogenesis, increases the ability of ATXN1 to interact with Tip60. Using a genetic approach, the biological relevance of the ATXN1/Tip60 interaction was assessed by crossing ATXN1[82Q] mice with Tip60+/-animals. Partial Tip60 loss increased Rora and Rora-mediated gene expression and delayed ATXN1[82]-mediated cerebellar degeneration during mid-stage disease progression. These results suggested a specific, temporal role for Tip60 during disease progression. We also showed that genetic background modulated ATXN1[82Q]-induced phenotypes. Of interest, these latter studies showed that some phenotypes are enhanced on a mixed background while others are suppressed.
Original language | English (US) |
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Article number | ddr108 |
Pages (from-to) | 2204-2212 |
Number of pages | 9 |
Journal | Human molecular genetics |
Volume | 20 |
Issue number | 11 |
DOIs | |
State | Published - Jun 2011 |
Bibliographical note
Funding Information:This work was supported by National Institutes of Health grants (NS022920, H.T.O.) and (NS055409, K.M.G.). Funding to pay the Open Access publication charges for this article was provided by a Ruth L. Kirschstein NRSA to K.M.G.