Partial loss of Tip60 slows mid-stage neurodegeneration in a spinocerebellar ataxia type 1 (SCA1) mouse model.

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.

journal_name

Hum Mol Genet

journal_title

Human molecular genetics

authors

Gehrking KM,Andresen JM,Duvick L,Lough J,Zoghbi HY,Orr HT

doi

10.1093/hmg/ddr108

subject

Has Abstract

pub_date

2011-06-01 00:00:00

pages

2204-12

issue

11

eissn

0964-6906

issn

1460-2083

pii

ddr108

journal_volume

20

pub_type

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