AHSA1/Hsp90α Complex Facilitates Microglial Mitophagy by Targeting TOMM70 in Parkinson Disease.

Abstract

Parkinson 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 was to gain a better understanding of microglial mitophagy in PD. A 1-methyl-1,2,3,6-tetrahydropyidine (MPTP)-induced PD mouse model was established and validated by behavior tests. Western blot and immunofluorescence (IF) analyses showed that autophagy was enhanced in MPTP-induced PD mice. IF, qRT-PCR, Western blot, and co-immunoprecipitation analyses also revealed that silencing of heat shock protein 90α (Hsp90α) protected against mitophagy in PD mice. In the microglia/dopaminergic neuron co-culture system, ELISA assay, transmission electron microscopy, JC-1 staining, measurement of ATP content, and Annexin V/propidium iodide staining showed that lack of Hsp90α in MPTP-treated microglia attenuated dopaminergic neuronal death via suppressing mitophagy. IF staining and co-immunoprecipitation confirmed that Hsp90α formed a complex with activator of Hsp90 ATPase activity 1 (AHSA1), and this complex targeted the mitochondrial molecular switch TOMM70 in microglia. The Hsp90α inhibitor geldanamycin and AHSA1 knockdown further revealed that the AHSA1/Hsp90α complex regulated microglial mitophagy by targeting TOMM70 in MPTP-treated microglia and PD mice. In conclusion, the AHSA1/Hsp90α complex facilitated microglial mitophagy by targeting TOMM70 in PD.