title: Degradation of amyotrophic lateral sclerosis-linked mutant Cu,Zn-superoxide dismutase proteins by macroautophagy and the proteasome.
abstract: Mutations in the Cu,Zn-superoxide dismutase (SOD1) gene cause approximately 20% of familial cases of amyotrophic lateral sclerosis (fALS). Accumulating evidence indicates that a gain of toxic function of mutant SOD1 proteins is the cause of the disease. It has also been shown that the ubiquitin-proteasome pathway plays a role in the clearance and toxicity of mutant SOD1. In this study, we investigated the degradation pathways of wild-type and mutant SOD1 in neuronal and nonneuronal cells. We provide here the first evidence that wild-type and mutant SOD1 are degraded by macroautophagy as well as by the proteasome. Based on experiments with inhibitors of these degradation pathways, the contribution of macroautophagy to mutant SOD1 clearance is comparable with that of the proteasome pathway. Using assays that measure cell viability and cell death, we observed that under conditions where expression of mutant SOD1 alone does not induce toxicity, macroautophagy inhibition induced mutant SOD1-mediated cell death, indicating that macroautophagy reduces the toxicity of mutant SOD1 proteins. We therefore propose that both macroautophagy and the proteasome are important for the reduction of mutant SOD1-mediated neurotoxicity in fALS. Inhibition of macroautophagy also increased SOD1 levels in detergent-soluble and -insoluble fractions, suggesting that both detergent-soluble and -insoluble SOD1 are degraded by macroautophagy. These findings may provide further insights into the mechanisms of pathogenesis of fALS.
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kabuta
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001343:Autophagy; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D013347:Subcellular Fractions / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D011500:Protein Synthesis Inhibitors; D013482:Superoxide Dismutase; D046988:Proteasome Endopeptidase Complex