New clearance system of abnormal protein in Polyglutammine disease

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Machado-Joseph disease (MJD)/Spinocerebellar ataxia type 3 (SCA3) is neurodegenerative disease which is caused by polyglutamine expansion in a responsible gene product, MJD1/Ataxin3. MJD1 has now been shown to undergo ubiquitylation and degradation by proteasome-dependent pathway. MJD1 with expanded polygiutamine tract was more resistant to degradation than normal MJD1. We established an in vitro system of ubiquitylation of MJD1, thereby biochemically purified activity to mediate polyubiquitylation of MJD1 from rabbit reticulocyte lysate. An AAA-family ATPase VCP was isolated from the active fraction, and found to binds to MJD1. Furthermore, UFD2a, a mammalian ubiquitin-chain assembly factor (E4), associated with VCP and induced polyubiquitylation of MJD1. UFD2a markedly promoted ubiquitylation and degradation of MJD1 with expanded polyglutamine tract, resulting in the clearance of MJD1 protein. In contrast, dominant-negative mutant UFD2a reduced the degradation rate of MJD1, leading to the formation of intracellular aggregation. In Drosophila model, overexpression of UFD2a significantly suppressed the neurodegeneration induced by expression of MJD1 with expanded polyglutamine tract. These findings suggest that E4 is a ratelimiting factor of degradation of pathologic polyglutamine-containing proteins, and may give a potential tool for gene therapy to control the clinical conditions of MJD