Abstract
Spinocerebellar ataxia type3 (SCA3, Machado-Joseph disease) is an inherited neurodegenerative disorder caused by an expansion of glutamine codon repeats of ataxin-3 gene. Expansion of polyglutamine repeats (polyQ) results in the misfolding of the ataxin-3 protein, thereby conferring a toxic gain of function. Previously, Yanagi and our group reported a new GTPase, CRAG that facilitates degradation of polyQ aggregates through the ubiquitin-proteasome pathway in cultured cells. To examine the potential of CRAG expression for treating SCA3, we produced transgenic mice (polyQ mice) expressing human ataxin-3 with an expanded polyglutamine stretch in Purkinje cells. The model mice showed poor dendritic arborization of Purkinje cells, a markedly atrophied cerebellum and severe ataxia. We analyzed the functional abnormalities of the cerebellum by patch-clamp. Synaptic transmission in Purkinje cells was substantially affected, and persistent multiple innervations of Purkinje cells by climbing fibers were observed in polyQ mouse. Furthermore, induction of long-term depression (LTD) at parallel fiber and Purkinje cell synapses was impaired. Despite of such severe phenotypes, cerebellar ataxia of polyQ mice was markedly improved after lentivector-mediated expression of CRAG in Purkinje cells. In this presentation, we show rescue of the electrophysiological properties in polyQ mutant cerebellum treated with CRAG. [J Physiol Sci. 2008;58 Suppl:S135]
