, 2005 and To et al., 1993). To understand the basis of SCA7 retinal degeneration and the reason for the selective loss of photoreceptor cells in this disease, we, and others, produced transgenic mice that recapitulated the SCA7 cone-rod dystrophy phenotype and found that SCA7

retinal degeneration results from altered transcription check details regulation (Helmlinger et al., 2006, La Spada et al., 2001 and Yoo et al., 2003). As the vast majority of CAG/polyQ disease proteins are well-known transcription factors or can function as transcription co-regulators (Riley and Orr, 2006), a role for transcription dysregulation in SCA7 is consistent with an emerging view of these disorders as “transcriptionopathies” (La Spada and Taylor, 2003). The existence of an interaction between ataxin-7 and a retinal transcription factor, known as CRX, suggested that ataxin-7 is a transcription factor (La Spada et al., 2001), and this was supported by demonstration of a functional nuclear localization signal in ataxin-7 (Chen et al., 2004). When studies of the yeast ortholog of ataxin-7, Sgf73, indicated

that Sgf73 is part of the ABT-199 molecular weight SAGA complex (Sanders et al., 2002), we, and others, found that ataxin-7 is a core component of the analogous coactivator complex in mammals, known as the STAGA (Spt3-Taf9-Ada-Gcn5-acetyltransferase) complex ( Helmlinger et al., 2004 and Palhan et al., 2005). STAGA is a transcriptional coactivator complex with histone acetyltransferase (HAT) activity ( Martinez et al., 2001). In addition to being part of the STAGA complex, yeast Sgf73 and mammalian ataxin-7 are respectively components of the Ubp8/USP22 deubiquitination complex ( Köhler et al., 2008 and Zhao et al., 2008). While the role of altered STAGA and USP22 deubiquitination complex function in SCA7 disease pathogenesis is unclear, recent studies of the related polyQ disorder SCA1 indicate that the polyQ expansion in ataxin-1

attenuates the formation and function of the Capicua transcription factor complex, contributing to SCA1 disease pathogenesis through a partial loss-of-function mechanism ( Chen et al., 2003 and Lim et al., 2008). Hence, polyQ disease may result from an alteration of normal function, Dipeptidyl peptidase combined with a gain-of-function mechanism, and in the case of SCA7, the native protein function of ataxin-7 appears critically important for chromatin remodeling at the level of histone acetylation and deubiquitination. In addition to the CAG/polyQ repeat diseases, at least three other subclasses of repeat expansion disease are recognized: loss-of-function repeat expansion diseases, RNA gain-of-function repeat disorders, and polyalanine gain-of-function repeat expansion diseases (La Spada and Taylor, 2010).