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, Angelo Poletti

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1604-1618
Number of pages15
JournalHuman Molecular Genetics
Volume16
Issue number13
DOIs
Publication statusPublished - Jul 2007

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Amyotrophic Lateral Sclerosis
Mutation
Motor Neurons
Proteasome Endopeptidase Complex
Cytoplasm
Superoxide Dismutase-1
Enzymes
Neurodegenerative Diseases
Transgenic Mice
DNA Damage
Oxidative Stress
Animal Models
Antioxidants

ASJC Scopus subject areas

  • Genetics

Cite this

Sau, D., De Biasi, S., Vitellaro-Zuccarello, L., Riso, P., Guarnieri, S., Porrini, M., ... Poletti, A. (2007). Mutation of SOD1 in ALS: A gain of a loss of function. Human Molecular Genetics, 16(13), 1604-1618. https://doi.org/10.1093/hmg/ddm110

Mutation of SOD1 in ALS : A gain of a loss of function. / Sau, Daniela; De Biasi, Silvia; Vitellaro-Zuccarello, Laura; Riso, Patrizia; Guarnieri, Serena; Porrini, Marisa; Simeoni, Silvia; Crippa, Valeria; Onesto, Elisa; Palazzolo, Isabella; Rusmini, Paola; Bolzoni, Elena; Bendotti, Caterina; Poletti, Angelo.

In: Human Molecular Genetics, Vol. 16, No. 13, 07.2007, p. 1604-1618.

Research output: Contribution to journalArticle

Sau, D, De Biasi, S, Vitellaro-Zuccarello, L, Riso, P, Guarnieri, S, Porrini, M, Simeoni, S, Crippa, V, Onesto, E, Palazzolo, I, Rusmini, P, Bolzoni, E, Bendotti, C & Poletti, A 2007, 'Mutation of SOD1 in ALS: A gain of a loss of function', Human Molecular Genetics, vol. 16, no. 13, pp. 1604-1618. https://doi.org/10.1093/hmg/ddm110
Sau D, De Biasi S, Vitellaro-Zuccarello L, Riso P, Guarnieri S, Porrini M et al. Mutation of SOD1 in ALS: A gain of a loss of function. Human Molecular Genetics. 2007 Jul;16(13):1604-1618. https://doi.org/10.1093/hmg/ddm110
Sau, Daniela ; De Biasi, Silvia ; Vitellaro-Zuccarello, Laura ; Riso, Patrizia ; Guarnieri, Serena ; Porrini, Marisa ; Simeoni, Silvia ; Crippa, Valeria ; Onesto, Elisa ; Palazzolo, Isabella ; Rusmini, Paola ; Bolzoni, Elena ; Bendotti, Caterina ; Poletti, Angelo. / Mutation of SOD1 in ALS : A gain of a loss of function. In: Human Molecular Genetics. 2007 ; Vol. 16, No. 13. pp. 1604-1618.
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