To confer the influence of Sir2 on pathogenesis of SCA3/MJD. GMR-GAL4 and Nrv2-GAL4 system SCA3/MJD transgenic Drosophila models were constructed by using the promoter GMR-GAL4 and Nrv2-GAL4 which drive target selective gene expression in cells of the developing eyes and motor neurons, respectively. Then, Sir2 protein was overexpressed in SCA3/MJD transgenic Drosophila models by genetic methods with or without in a background of RNAi knockdown of Atg7. Overexpression of endogenous Drosophila Sir2 not only notably suppresses the neurotoxicity of MJDtr-Q78 protein, but also significantly improves the movement ability of flies. Moreover, RNAi knockdown of Atg7 significantly Sir2's protection against SCA3/MJD Drosophila. We confirmed that overexpression of Sir2 could protect SCA3/MJD Drosophila models, and the protection role of Sir2 on SCA3/MJD Drosophila models is autophagy-dependent.