AHSA1/Hsp90α complex facilitates microglial mitophagy by targeting TOMM70 in Parkinson's disease.

Abstract

Parkinson's disease (PD) is a commonly diagnosed neurodegenerative disease with rising prevalence globally. However, the pathology of PD remains largely undefined. The aim of this study is to get better understanding of microglial mitophagy in PD. 1-methyl-1,2,3,6-tetrahydropyidine (MPTP)-induced PD mouse model was established and validated by behavior tests. Western blot and immunofluorescent (IF) showed that autophagy was enhanced in MPTP-induced PD mice. IF, qRT-PCR, western blot and co-immunoprecipitation (co-IP) also revealed that silencing of Hsp90α protected against mitophagy in PD mice. In microglia/DA neurons co-culture system, ELISA assay, Transmission Electron Microscopy (TEM), JC-1 staining, measurement of ATP content and Annexin V/PI staining showed that lack of Hsp90α in MPTP-treated microglia attenuated DA neuronal death via suppressing mitophagy. IF staining and co-IP confirmed that Hsp90α formed a complex with AHSA1, and this complex targeted the mitochondrial molecular switch TOMM70 in microglia. Hsp90α inhibitor geldanamycin (GA) and AHSA1 knockdown further revealed that AHSA1/Hsp90α complex regulated microglial mitophagy by targeting TOMM70 in MPTP-treated microglia and PD mice. In conclusion, AHSA1/Hsp90α complex facilitated microglial mitophagy by targeting TOMM70 in PD.