title: Mutation of SOD1 in ALS: a gain of a loss of function.
abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by motoneuron loss. Some familial cases (fALS) are linked to mutations of superoxide dismutase type-1 (SOD1), an antioxidant enzyme whose activity is preserved in most mutant forms. Owing to the similarities in sporadic and fALS forms, mutant SOD1 animal and cellular models are a useful tool to study the disease. In transgenic mice expressing either wild-type (wt) human SOD1 or mutant G93A-SOD1, we found that wtSOD1 was present in cytoplasm and in nuclei of motoneurons, whereas mutant SOD1 was mainly cytoplasmic. Similar results were obtained in immortalized motoneurons (NSC34 cells) expressing either wtSOD1 or G93A-SOD1. Analyzing the proteasome activity, responsible for misfolded protein clearance, in the two subcellular compartments, we found proteasome impairment only in the cytoplasm. The effect of G93A-SOD1 exclusion from nuclei was then analyzed after oxidative stress. Cells expressing G93A-SOD1 showed a higher DNA damage compared with those expressing wtSOD1, possibly because of a loss of nuclear protection. The toxicity of mutant SOD1 might, therefore, arise from an initial misfolding (gain of function) reducing nuclear protection from the active enzyme (loss of function in the nuclei), a process that may be involved in ALS pathogenesis.
authors.affiliation: Institute of Endocrinology, Center of Excellence on Neurodegenerative Diseases, Division of Human Nutrition, University of Milan, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Sau
authors.forename: Silvia
authors.initials: S
authors.lastname: De Biasi
authors.forename: Laura
authors.initials: L
authors.lastname: Vitellaro-Zuccarello
authors.forename: Patrizia
authors.initials: P
authors.lastname: Riso
authors.forename: Serena
authors.initials: S
authors.lastname: Guarnieri
authors.forename: Marisa
authors.initials: M
authors.lastname: Porrini
authors.forename: Silvia
authors.initials: S
authors.lastname: Simeoni
authors.forename: Valeria
authors.initials: V
authors.lastname: Crippa
authors.forename: Elisa
authors.initials: E
authors.lastname: Onesto
authors.forename: Isabella
authors.initials: I
authors.lastname: Palazzolo
authors.forename: Paola
authors.initials: P
authors.lastname: Rusmini
authors.forename: Elena
authors.initials: E
authors.lastname: Bolzoni
authors.forename: Caterina
authors.initials: C
authors.lastname: Bendotti
authors.forename: Angelo
authors.initials: A
authors.lastname: Poletti
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009154:Mutation; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics*
chemical_list: D013482:Superoxide Dismutase; D046988:Proteasome Endopeptidase Complex; D010100:Oxygen