Studying the Mechanism of Neuronal Dysfunction in SCA7

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Spinocerebellar ataxia 7 (SCA7) is a one of a growing group of neurodegenerative and mental disorders caused by a CAG expansion; this expansion occurs in the SCA7 gene, which encodes ataxin-7. In addition to cerebellar signs and decreased visual acuity, SCA7 patients can suffer from cognitive dysfunction and behavioral problems. Previous work in our laboratory resulted in generation of Sca7266Q/SQ knock-in (KI) and Sca7 knock-out (KO) mouse models. Sca7266Q/SQmice replicate all of the features of infantile SCA7 and have decreased post-tetantic potentiation (PTP) in hippocampal area CA1. Sca7 KO mice are unaffected and behaviorally normal, but exhibit increased PTP. Given evidence for transcriptional misregulation in Sca7266Q/5Q mice, the overall hypothesis is that ataxin-7 causes alterations in gene expression that result in the hippocampal and cerebellar phenotypes. To test this hypothesis, the extent and time course of synaptic dysfunction in mutant mice will be determined and the expression levels of candidates will be measured. In a complementary unbiased approach, expression profiling will be carried out and correlated with phenotype onset and progression. Finally, a practical approach will be taken by conducting trials of histone deacetylase;266Q/5Q (HDAC) inhibitors in Sca7 mice. These studies will provide novel insight into mechanisms of pathogenesis that occur at the level of the synapse in SCA7, and will be crucial in evaluating the efficacy of a class of therapeutic compounds in treatment of this and other polyglutamine diseases.