Journal Article

Mutation of SOD1 in ALS: a gain of a loss of function

Daniela Sau, Silvia De Biasi, Laura Vitellaro-Zuccarello, Patrizia Riso, Serena Guarnieri, Marisa Porrini, Silvia Simeoni, Valeria Crippa, Elisa Onesto, Isabella Palazzolo, Paola Rusmini, Elena Bolzoni, Caterina Bendotti and Angelo Poletti

in Human Molecular Genetics

Volume 16, issue 13, pages 1604-1618
Published in print July 2007 | ISSN: 0964-6906
Published online May 2007 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddm110
Mutation of SOD1 in ALS: a gain of a loss of function

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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.

Journal Article.  9467 words.  Illustrated.

Subjects: Genetics and Genomics

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