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Cellular Redox Systems Impact the Aggregation of Cu,Zn Superoxide Dismutase Linked to Familial Amyotrophic Lateral Sclerosis

Álvarez-Zaldiernas, Cristina ; Lu, Jun ; Zheng, Yujuan ; Yang, Hongqian ; Blasi, Juan ; Solsona, Carles ; Holmgren, Arne

The Journal of biological chemistry, 2016-08, Vol.291 (33), p.17197-17208 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Cellular Redox Systems Impact the Aggregation of Cu,Zn Superoxide Dismutase Linked to Familial Amyotrophic Lateral Sclerosis
Autor: Álvarez-Zaldiernas, Cristina ; Lu, Jun ; Zheng, Yujuan ; Yang, Hongqian ; Blasi, Juan ; Solsona, Carles ; Holmgren, Arne
Assuntos: ALS (Lou Gehrig disease) ; Amino Acid Substitution ; Amyotrophic lateral sclerosis ; Amyotrophic Lateral Sclerosis - enzymology ; Amyotrophic Lateral Sclerosis - genetics ; Animals ; Cell Line, Tumor ; cysteine 111 ; Esclerosi lateral amiotròfica ; Estrès oxidatiu ; glutaredoxin ; Glutaredoxins - genetics ; Glutaredoxins - metabolism ; glutathione ; Humans ; Malalties neurodegeneratives ; Medicin och hälsovetenskap ; Mutation, Missense ; Neurodegenerative Diseases ; Oxidation-Reduction ; Oxidative Stress ; protein aggregation ; Protein Aggregation, Pathological - enzymology ; Protein Aggregation, Pathological - genetics ; Protein Folding ; Protein Structure and Folding ; Rats ; reduction-oxidation (redox) ; SOD1 ; Superoxide Dismutase-1 - genetics ; Superoxide Dismutase-1 - metabolism ; thiol ; thioredoxin ; Thioredoxins - genetics ; Thioredoxins - metabolism
É parte de: The Journal of biological chemistry, 2016-08, Vol.291 (33), p.17197-17208
Descrição: Protein misfolding is implicated in neurodegenerative diseases such as ALS, where mutations of superoxide dismutase 1 (SOD1) account for about 20% of the inherited mutations. Human SOD1 (hSOD1) contains four cysteines, including Cys57 and Cys146, which have been linked to protein stability and folding via forming a disulfide bond, and Cys6 and Cys111 as free thiols. But the roles of the cellular oxidation-reduction (redox) environment in SOD1 folding and aggregation are not well understood. Here we explore the effects of cellular redox systems on the aggregation of hSOD1 proteins. We found that the known hSOD1 mutations G93A and A4V increased the capability of the thioredoxin and glutaredoxin systems to reduce hSOD1 compared with wild-type hSOD1. Treatment with inhibitors of these redox systems resulted in an increase of hSOD1 aggregates in the cytoplasm of cells transfected with mutants but not in cells transfected with wild-type hSOD1 or those containing a secondary C111G mutation. This aggregation may be coupled to changes in the redox state of the G93A and A4V mutants upon mild oxidative stress. These results strongly suggest that the thioredoxin and glutaredoxin systems are the key regulators for hSOD1 aggregation and may play critical roles in the pathogenesis of ALS.
Editor: United States: Elsevier Inc
Idioma: Inglês

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Cellular Redox Systems Impact the Aggregation of Cu,Zn Superoxide Dismutase Linked to Familial Amyotrophic Lateral Sclerosis

Álvarez-Zaldiernas, Cristina ; Lu, Jun ; Zheng, Yujuan ; Yang, Hongqian ; Blasi, Juan ; Solsona, Carles ; Holmgren, Arne

United States: Elsevier Inc

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