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Parkin Protects Against Misfolded SOD1 Toxicity by Promoting Its Aggresome Formation and Autophagic Clearance

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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.

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Acknowledgments

We thank Dr. Richard Palmiter for providing breeding pairs of parkin knockout mice and Drs. Haining Zhu and Do Hee Li for providing SOD1 plasmids. This work was supported by the National Institutes of Health (NIH) Grants to C.Y. (NS074620), L.L. (GM103613), L.S.C. (AG034126 and NS093550), and pilot grant awards from NIH-funded Emory Udall Parkinson’s Disease Center (P50 NS071669) and Emory University Research Committee to L.S.C. (SK38167) and L.L. (SK46673). C.Y. was a trainee supported by NIH Pharmacological Sciences Training Grant (T32 GM008602).

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  1. Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Cheryl Yung, Di Sha, Lian Li & Lih-Shen Chin

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Yung, C., Sha, D., Li, L. et al. Parkin Protects Against Misfolded SOD1 Toxicity by Promoting Its Aggresome Formation and Autophagic Clearance. Mol Neurobiol 53, 6270–6287 (2016). https://doi.org/10.1007/s12035-015-9537-z

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