文章基本信息

标题：Endoplasmic reticulum stress leads to accumulation of wild-type SOD1 aggregates associated with sporadic amyotrophic lateral sclerosis
作者：Danilo B. Medinas ; Pablo Rozas ; Francisca Martínez Traub 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2018
卷号：115
期号：32
页码：8209-8214
DOI：10.1073/pnas.1801109115
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Abnormal modifications to mutant superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (fALS). Misfolding of wild-type SOD1 (SOD1^WT) is also observed in postmortem tissue of a subset of sporadic ALS (sALS) cases, but cellular and molecular mechanisms generating abnormal SOD1^WT species are unknown. We analyzed aberrant human SOD1^WT species over the lifetime of transgenic mice and found the accumulation of disulfide–cross-linked high–molecular-weight SOD1^WT aggregates during aging. Subcellular fractionation of spinal cord tissue and protein overexpression in NSC-34 motoneuron-like cells revealed that endoplasmic reticulum (ER) localization favors oxidation and disulfide-dependent aggregation of SOD1^WT. We established a pharmacological paradigm of chronic ER stress in vivo, which recapitulated SOD1^WTaggregation in young transgenic mice. These species were soluble in nondenaturing detergents and did not react with a SOD1 conformation-specific antibody. Interestingly, SOD1^WT aggregation under ER stress correlated with astrocyte activation in the spinal cord of transgenic mice. Finally, the disulfide–cross-linked SOD1^WT species were also found augmented in spinal cord tissue of sALS patients, correlating with the presence of ER stress markers. Overall, this study suggests that ER stress increases the susceptibility of SOD1^WT to aggregate during aging, operating as a possible risk factor for developing ALS.
关键词：amyotrophic lateral sclerosis ; wild-type SOD1 ; ER stress ; aging ; protein aggregation