Non-cell autonomous neurodegeneration in SCA7

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DESCRIPTION (provided by applicant): Spinocerebellar Ataxia Type 7 (SCA7) is a dominantly inherited form of olivopontocerebellar atrophy caused by a CAG repeat expansion within the coding region of the gene for the ataxin-7 protein. Despite identification of the precise genetic abnormality associated with this disease, the mechanism by which the polyglutamine expansion in ataxin-7 causes selective neurotoxicity is not known. In a transgenic mouse model of SCA7 (polyglutamine expanded ataxin-7 expressed under the control of the prion protein promoter), degeneration of the cerebellar Purkinje cells (PC's) occurs in a non-cell autonomous fashion. Ultra-structural analysis of this SCA7 model revealed a pattern of PC degeneration observed when PC injury is caused by excitotoxic insult. The ultra-structural evaluation of SCA7 mice also revealed evidence for pathology in several cerebellar elements including loss of climbing fiber input and dramatic changes in the morphology of Bergmann glia. Additionally, ataxic SCA7 mice demonstrate loss of trophic factors normally supplied by climbing fibers and Bergmann glia. Taken together, these observations support the hypothesis that PC degeneration in SCA7 is secondary to an altered extra-cellular environment. In this proposal we plan to address the question of how mutant ataxin-7 alters the PC environment resulting in PC degeneration. First, we will perform comprehensive behavioral, histological and ultra structural analysis of the natural history of PC degeneration in SCA7 knock-in mice and mice expressing the mutant protein in specific cellular populations of the cerebellum using a conditional inactivation strategy. Second, two specific aspects of the extracellular environment will be examined: Neurotrophic factors and Neurotransmitter homeostasis. The specific alterations in the cerebellar environment that are associated with the onset of the disease phenotype in transgenic and knock-in mouse models of SCA7 will be further characterized. Additionally, experiments attempting to normalize the cerebellar environment in SCA7 mice will be initiated in order to determine if restoring neurotrophic support or preventing excitotoxicty will subsequently delay or prevent the disease phenotype. PUBLIC HEALTH RELEVANCE: The overriding objective of this proposal is to further define the pathogenesis of spinocerebellar ataxia type 7 (SCA7), an inherited neurodegenerative disease. The long-term aim is to identify potential targets for therapeutic intervention in this devastating neurodegenerative disease.