title: BAG2 Gene-mediated Regulation of PINK1 Protein Is Critical for Mitochondrial Translocation of PARKIN and Neuronal Survival.
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.
authors.affiliation: From the Department of Cellular and Molecular Medicine, Brain and Mind Research Institute, and.
authors.forename: Dianbo
authors.initials: D
authors.lastname: Qu
authors.affiliation: From the Department of Cellular and Molecular Medicine, Brain and Mind Research Institute, and.
authors.forename: Ali
authors.initials: A
authors.lastname: Hage
authors.affiliation: From the Department of Cellular and Molecular Medicine, Brain and Mind Research Institute, and.
authors.forename: Katie
authors.initials: K
authors.lastname: Don-Carolis
authors.affiliation: From the Department of Cellular and Molecular Medicine, Brain and Mind Research Institute, and.
authors.forename: En
authors.initials: E
authors.lastname: Huang
authors.affiliation: From the Department of Cellular and Molecular Medicine, Brain and Mind Research Institute, and.
authors.forename: Alvin
authors.initials: A
authors.lastname: Joselin
authors.affiliation: From the Department of Cellular and Molecular Medicine, Brain and Mind Research Institute, and.
authors.forename: Farzaneh
authors.initials: F
authors.lastname: Safarpour
authors.affiliation: From the Department of Cellular and Molecular Medicine, Brain and Mind Research Institute, and.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Marcogliese
authors.affiliation: From the Department of Cellular and Molecular Medicine, Brain and Mind Research Institute, and.
authors.forename: Maxime W C
authors.initials: MW
authors.lastname: Rousseaux
authors.affiliation: From the Department of Cellular and Molecular Medicine, Brain and Mind Research Institute, and.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Hewitt
authors.affiliation: From the Department of Cellular and Molecular Medicine, Brain and Mind Research Institute, and.
authors.forename: Tianwen
authors.initials: T
authors.lastname: Huang
authors.affiliation: From the Department of Cellular and Molecular Medicine, Brain and Mind Research Institute, and.
authors.forename: Doo-Soon
authors.initials: DS
authors.lastname: Im
authors.affiliation: From the Department of Cellular and Molecular Medicine, Brain and Mind Research Institute, and.
authors.forename: Steve
authors.initials: S
authors.lastname: Callaghan
authors.affiliation: Brain and Mind Research Institute, and Ottawa Institute of Systems Biology, University of Ottawa, Ottawa K1H 8M5, Ontario, Canada.
authors.forename: Danielle
authors.initials: D
authors.lastname: Dewar-Darch
authors.affiliation: Brain and Mind Research Institute, and Ottawa Institute of Systems Biology, University of Ottawa, Ottawa K1H 8M5, Ontario, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Figeys
authors.affiliation: From the Department of Cellular and Molecular Medicine, Brain and Mind Research Institute, and.
authors.forename: Ruth S
authors.initials: RS
authors.lastname: Slack
authors.affiliation: From the Department of Cellular and Molecular Medicine, Brain and Mind Research Institute, and dpark@uottawa.ca.
authors.forename: David S
authors.initials: DS
authors.lastname: Park
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D063306:Mitophagy / Q000235:genetics; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D021381:Protein Transport; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000099202:PTEN-Induced Putative Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018832:Molecular Chaperones; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C534046:Bag2 protein, mouse; C111567:parkin protein
keywords: Parkinson disease; cell death; neurodegenerative disease; translocation; ubiquitylation (ubiquitination)