Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant inherited disorder characterized by ataxia and retinal degeneration. SCA7 is caused by an expansion of a CAG / polyglutamine repeat in the ataxin-7 gene, but is unique among the polyglutamine repeat diseases because the phenotype includes an unusual form of retinal degeneration, known as cone-rod dystrophy. We have become interested in SCA7 cone-rod dystrophy for two reasons: 1) An understanding of the molecular basis of SCA7 retinal degeneration may provide insight into how other polyglutamine repeat expansions produce neurodegeneration, and 2) A mouse model of SCA7 cone-rod dystrophy provides us with an opportunity to develop an effective therapy for this retinal degeneration. Our preliminary studies have focused on the production and characterization of a mouse model of SCA7 cone-rod dystrophy. By directing transgenic expression of the ataxin-7 polyglutamine repeat expansion to nuclear layers of the retina, we have been able to faithfully recapitulate the cone-rod dystrophy type of retinal degeneration seen in SCA7 patients in a mouse model. Furthermore, we have found evidence to support the hypothesis that polyglutamine-expanded ataxin-7 causes SCA7 cone-rod dystrophy by interfering with the transactivation function of a nuclear transcription factor, the cone-rod homeodomain protein (CRX). Using the resources that we have generated, we now wish to advance our understanding of SCA7 retinal degeneration and use this knowledge to develop an effective therapy for SCA7 retinal degeneration. To accomplish these goals, we will further characterize the CRX - ataxin-7 interaction and will define the amino acid sequences on CRX and on ataxin-7 that mediate this interaction. We will use transgenesis to determine if CRX transcription interference can fully account for the SCA7 cone-rod dystrophy phenotype observed in our mouse model. We will seek to identify additional ataxin-7 interacting proteins and amino acid domains - not only as a contingency if CRX transcription interference is not responsible for SCA7 retinal degeneration, but also to identify candidates for involvement in CRX and non-CRX disease pathways in the retina and brainstem. Using retinal gene transfer, we will try to prevent and to reverse the development of SCA7 cone-rod dystrophy in our transgenic mouse model. Finally, we will attempt to determine the pattern of gene expression alterations occurring in SCA7 retinal degeneration and then compare these expression alterations to those occurring in degenerating SCA7 cerebellar tissues by performing microarray analysis of our SCA7 transgenic mice.
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