title: Parkin Protects Against Misfolded SOD1 Toxicity by Promoting Its Aggresome Formation and Autophagic Clearance.
abstract: Mutations in Cu/Zn superoxide dismutase (SOD1) cause autosomal dominant amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease with no effective treatment. Despite ample evidence indicating involvement of mutation-induced SOD1 protein misfolding and aggregation in ALS pathogenesis, the molecular mechanisms that control cellular management of misfolded, aggregation-prone SOD1 mutant proteins remain unclear. Here, we report that parkin, an E3 ubiquitin-protein ligase which is linked to Parkinson's disease, is a novel regulator of cellular defense against toxicity induced by ALS-associated SOD1 mutant proteins. We find that parkin mediates K63-linked polyubiquitination of SOD1 mutants in cooperation with the UbcH13/Uev1a E2 enzyme and promotes degradation of these misfolded SOD1 proteins by the autophagy-lysosome system. In response to strong proteotoxic stress associated with proteasome impairment, parkin promotes sequestration of misfolded and aggregated SOD1 proteins to form perinuclear aggresomes, regulates positioning of lysosomes around misfolded SOD1 aggresomes, and facilitates aggresome clearance by autophagy. Our findings reveal parkin-mediated cytoprotective mechanisms against misfolded SOD1 toxicity and suggest that enhancing parkin-mediated cytoprotection may provide a novel therapeutic strategy for treating ALS.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Yung
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Sha
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Lian
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, 30322, USA. chinl@pharm.emory.edu.
authors.forename: Lih-Shen
authors.initials: LS
authors.lastname: Chin
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D019610:Cytoprotection / Q000187:drug effects; D017353:Gene Deletion; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D018345:Mice, Knockout; D050505:Mutant Proteins / Q000633:toxicity; D000066829:Neuroprotection / Q000187:drug effects; D025821:Polyubiquitin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D066329:Protein Aggregates / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D013482:Superoxide Dismutase / Q000633:toxicity*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D050505:Mutant Proteins; D066329:Protein Aggregates; D025821:Polyubiquitin; D013482:Superoxide Dismutase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex; D008239:Lysine
keywords: Aggresome; Amyotrophic lateral sclerosis; Autophagy; Cu/Zn superoxide dismutase; Lysosome; Parkin