Degradation of Amyotrophic Lateral Sclerosis-linked Mutant Cu,Zn-Superoxide Dismutase Proteins by Macroautophagy and the Proteasome

• Published in: The Journal of biological chemistry Vol. 281; no. 41; pp. 30524 - 30533
• Main Authors: Kabuta, Tomohiro, Suzuki, Yasuyuki, Wada, Keiji
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.10.2006; American Society for Biochemistry and Molecular Biology
• Subjects: Amyotrophic Lateral Sclerosis - genetics; Animals; Antibiotics, Antineoplastic - pharmacology; Autophagy; Chlorocebus aethiops; COS Cells; Humans; Mice; Mutation; Neurons - metabolism; Proteasome Endopeptidase Complex - metabolism; Protein Synthesis Inhibitors - pharmacology; Subcellular Fractions - metabolism; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M603337200

Mutations in the Cu,Zn-superoxide dismutase (SOD1) gene cause ∼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.