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

Kristin M. Gehrking, J. Michael Andresen, Lisa Duvick, John Lough, Huda Y. Zoghbi, Harry T Orr

Research output: Contribution to journalArticle

35 Citations (Scopus)

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 languageEnglish (US)
Article numberddr108
Pages (from-to)2204-2212
Number of pages9
JournalHuman molecular genetics
Volume20
Issue number11
DOIs
StatePublished - Jun 1 2011

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tat Gene Products
Spinocerebellar Ataxias
Disease Progression
HMGB Proteins
Ataxin-1
Phenotype
Acetyltransferases
Retinoids
Neurodegenerative Diseases

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Partial loss of Tip60 slows mid-stage neurodegeneration in a spinocerebellar ataxia type 1 (SCA1) mouse model. / Gehrking, Kristin M.; Andresen, J. Michael; Duvick, Lisa; Lough, John; Zoghbi, Huda Y.; Orr, Harry T.

In: Human molecular genetics, Vol. 20, No. 11, ddr108, 01.06.2011, p. 2204-2212.

Research output: Contribution to journalArticle

Gehrking, Kristin M. ; Andresen, J. Michael ; Duvick, Lisa ; Lough, John ; Zoghbi, Huda Y. ; Orr, Harry T. / Partial loss of Tip60 slows mid-stage neurodegeneration in a spinocerebellar ataxia type 1 (SCA1) mouse model. In: Human molecular genetics. 2011 ; Vol. 20, No. 11. pp. 2204-2212.
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