title: Muscle cells and motoneurons differentially remove mutant SOD1 causing familial amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal motoneuronal disease which occurs in sporadic or familial forms, clinically indistinguishable. About 15% of familial ALS cases are linked to mutations of the superoxide dismutase 1 (SOD1) gene that may induce misfolding in the coded protein, exerting neurotoxicity to motoneurons. However, other cell types might be target of SOD1 toxicity, because muscle-restricted expression of mutant SOD1 correlates with muscle atrophy and motoneurons death. We analysed the molecular behaviour of mutant SOD1 in motoneuronal NSC34 and muscle C2C12 cells. We found that misfolded mutant SOD1 clearance is much more efficient in muscle C2C12 than in motoneuronal NSC34 cells. Mutant SOD1 forms aggregates and impairs the proteasome only in motoneuronal NSC34 cells. Interestingly, NSC34 cells expressing mutant SOD1 are more sensitive to a superoxide-induced oxidative stress. Moreover, in muscle C2C12 cells mutant SOD1 remains soluble even when proteasome is inhibited with MG132. The higher mutant SOD1 clearance in muscle cells correlates with a more efficient proteasome activity, combined with a robust autophagy activation. Therefore, muscle cells seem to better manage misfolded SOD1 species, not because of an intrinsic property of the mutant protein, but in function of the cell environment, indicating also that the SOD1 toxicity at muscle level may not directly depend on its aggregation rate.
authors.affiliation: Dipartimento di Endocrinologia, Fisiopatologia e Biologia Applicata, Università degli Studi di Milano, Milano, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Onesto
authors.forename: Paola
authors.initials: P
authors.lastname: Rusmini
authors.forename: Valeria
authors.initials: V
authors.lastname: Crippa
authors.forename: Nicola
authors.initials: N
authors.lastname: Ferri
authors.forename: Arianna
authors.initials: A
authors.lastname: Zito
authors.forename: Mariarita
authors.initials: M
authors.lastname: Galbiati
authors.forename: Angelo
authors.initials: A
authors.lastname: Poletti
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D002461:Cell Line, Transformed; D006801:Humans; D009046:Motor Neurons / Q000201:enzymology* / Q000473:pathology; D032342:Muscle Cells / Q000201:enzymology* / Q000473:pathology; D009154:Mutation / Q000502:physiology*; D032446:Myoblasts / Q000201:enzymology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D061988:Proteasome Inhibitors; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D046988:Proteasome Endopeptidase Complex