BAG2 Gene-mediated Regulation of PINK1 Protein Is Critical for Mitochondrial Translocation of PARKIN and Neuronal Survival |
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| Authors: | Dianbo Qu Ali Hage Katie Don-Carolis En Huang Alvin Joselin Farzaneh Safarpour Paul C Marcogliese Maxime W C Rousseaux Sarah J Hewitt Tianwen Huang Doo-Soon Im Steve Callaghan Danielle Dewar-Darch Daniel Figeys Ruth S Slack David S Park |
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| Institution: | From the ‡Department of Cellular and Molecular Medicine.;§Brain and Mind Research Institute, and ;¶Ottawa Institute of Systems Biology, University of Ottawa, Ottawa K1H 8M5, Ontario, Canada |
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| Abstract: | Emerging evidence has demonstrated a growing genetic component in Parkinson disease (PD). For instance, loss-of-function mutations in PINK1 or PARKIN can cause autosomal recessive PD. Recently, PINK1 and PARKIN have been implicated in the same signaling pathway to regulate mitochondrial clearance through recruitment of PARKIN by stabilization of PINK1 on the outer membrane of depolarized mitochondria. The precise mechanisms that govern this process remain enigmatic. In this study, we identify Bcl2-associated athanogene 2 (BAG2) as a factor that promotes mitophagy. BAG2 inhibits PINK1 degradation by blocking the ubiquitination pathway. Stabilization of PINK1 by BAG2 triggers PARKIN-mediated mitophagy and protects neurons against 1-methyl-4-phenylpyridinium-induced oxidative stress in an in vitro cell model of PD. Collectively, our findings support the notion that BAG2 is an upstream regulator of the PINK1/PARKIN signaling pathway. |
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| Keywords: | cell death neurodegenerative disease Parkinson disease translocation ubiquitylation (ubiquitination) |
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