Effection And Mechanism Of PINK1Knock-down On The Neurodegeneration Of SCA3/MJD Transgenic Drosophila

Objective:To study the role of PD-related proteins on the pathogenesis of SCA3/MJD, then to verify whether the role of PINK1knock-down which suppresses the neurodegeneration of SCA3/MJD transgenic drosophila is dependent on ubiquitin-proteasome pathway and aggresome-autophagy pathway.Methods:We used the drosophila with PD-related proteins to intervene SCA3/MJD transgenic drosophila which genotype was GMR-GAL4, UAS-MJDtr-Q78/cyo respectively, and observed the feature of the above drosophila eyes under light microscope and electron microscope, Furthermore, by inhibiting ubiquitin-proteasome pathway or aggresome-autophagy pathway, we observed the eyes feature of PINK1knocked-down on the neurodegeneration of SCA3/MJD transgenic drosophila.Results:On the one hand, the overexpression or complete knock-out of PINKl remarkablely increased the neurodegeneration of SCA3/MJD transgenic drosophila, but knock-down of PINK1predominantly improved the neurodegeneration of SCA3/MJD transgenic drosophila; on the other hand, the overexpression, knock-down or mutation of Parkin all increased the neurodegeneration of SCA3/MJD transgenic drosophila. Through inhibiting the ubiquitin-proteasome pathway or aggresome-autophagy pathway,we found that the protection role of PINK1knock-down on the neurodegeneration of SCA3/MJD transgenic drosophila was notably decreased.Conclusions:On the one hand, PINK1and Parkin participated in the regulation of toxic mechanism of mutant ataxin-3, the overexpression or complete knock-out of PINK1remarkablely increased the toxicity of mutant ataxin-3, but knock-down of PINK1through ubiquitin-proteasome pathway and aggresome-autophagy pathway reduced the neurotoxicity of mutant ataxin-3to inhibit the neurodegeneration of SCA3/MJD transgenic drosophila; on the other hand, the changed expression level or mutation of Parkin increased the toxicity of mutant ataxin-3, it is implicated that the nomal function of Parkin is essencial to maintain the neuron stability of SCA3/MJD transgenic drosophila.