Spinocerebellar ataxia type 7 (SCA7) is an inherited neurological disorder characterized by cerebellar and retinal degeneration. SCA7, caused by CAG/polyglutamine (polyQ) repeat expansions in the ataxin-7 gene, is one of nine polyQ neurodegenerative disorders. In our previously funded research grant, we proposed to determine the molecular basis of SCA7 disease pathogenesis, and to use that knowledge to develop meaningful therapies for SCA7. Among the crucial advances that we have made toward achieving this goal is our identification of ataxin-7's normal function as a transcription factor. The discovery of ataxin-7 as a core component of the STAGA co-activator complex has led to a model of SCA7 retinal degeneration involving altered function of this polyQ disease protein. We also have taken advantage of an occurrence of non-cell autonomous neurodegeneration in our SCA7 mouse model to begin to define the cellular basis of polyQ disease pathogenesis. This work has highlighted the potential importance of glial dysfunction in SCA7, and has underscored the need for a better understanding of the role of different cell types in neurodegeneration. Building on the information that we have acquired during this funding term, we propose to continue our studies of SCA7 pathogenesis and therapy development through the pursuit of two interdependent investigations. First, we will test the hypothesis that transcriptional dysregulation is the major cause of SCA7 retinal degeneration. We will determine if altered STAGA co-activator complex function underlies SCA7 retinal degeneration through parallel ChlP-CHIP - microarray studies and by testing the importance of GCN5 - ataxin-7 interaction for SCA7 pathogenesis. We will also examine if modulation of polyQ-ataxin-7 transcription dysregulation by ataxin-7 shRNA knock-down could be an effective therapy for SCA7 retinal degeneration. Second, we will test the hypothesis that delineation of the contribution of different cell types to SCA7 neurodegeneration is required for understanding the basis of SCA7 and for designing rationale therapies to treat SCA7. This will be done by developing a conditional inactivation SCA7 mouse model to determine cell type contribution and reversibility of SCA7 retinal and cerebellar degeneration. As our published results implicate impaired glutamate transport in SCA7, we will assess modulators of glutamate transporter expression as a potential treatment for SCA7 in the context of cell contribution findings.
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