Amyotrophic lateral sclerosis 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. Due 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, while mutant SOD1 was mainly cytoplasmic. Similar results were obtained in immortalized motoneurons (NSC34 cells) expressing either wt or G93A-SOD1. Analysing 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 to 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.
Mutation of the SOD1 in ALS : a gain of a loss of function / D. Sau, S. De Biasi, L. Vitellaro-Zuccarello, P. Riso, S. Guarnieri, M. Porrini, S. Simeoni, V. Crippa, E. Onesto, I. Palazzolo, P. Rusmini, E. Bolzoni, C. Bendotti, A. Poletti. - In: HUMAN MOLECULAR GENETICS. - ISSN 0964-6906. - 16:13(2007), pp. 1604-1618.
|Titolo:||Mutation of the SOD1 in ALS : a gain of a loss of function|
SAU, DANIELA (Primo)
DE BIASI, SILVIA (Secondo)
POLETTI, ANGELO (Ultimo)
|Settore Scientifico Disciplinare:||Settore BIO/09 - Fisiologia|
Settore BIO/06 - Anatomia Comparata e Citologia
Settore BIO/16 - Anatomia Umana
Settore BIO/13 - Biologia Applicata
|Data di pubblicazione:||2007|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1093/hmg/ddm110|
|Appare nelle tipologie:||01 - Articolo su periodico|