Amyotrophic lateral sclerosis(ALS)is characterized by adult-onset progressive degeneration of upper and lower motor neurons.Increasing numbers of genes are found to be associated with ALS;among those,the first identif...Amyotrophic lateral sclerosis(ALS)is characterized by adult-onset progressive degeneration of upper and lower motor neurons.Increasing numbers of genes are found to be associated with ALS;among those,the first identified gene,SOD1 coding a Cu/Zn-superoxide dismutase protein(SOD1),has been regarded as the gold standard in the research on a pathomechanism of ALS.Abnormal accumulation of misfolded SOD1 in affected spinal motor neurons has been established as a pathological hallmark of ALS caused by mutations in SOD1(SOD1-ALS).Nonetheless,the involvement of wild-type SOD1 remains quite controversial in the pathology of ALS with no SOD1 mutations(non-SOD1 ALS),which occupies more than 90%of total ALS cases.In vitro studies have revealed post-translationally controlled misfolding and aggregation of wild-type as well as of mutant SOD1 proteins;therefore,SOD1 proteins could be a therapeutic target not only in SOD1-ALS but also in more prevailing cases,non-SOD1 ALS.In order to search for evidence on misfolding and aggregation of wild-type SOD1 in vivo,we reviewed pathological studies using mouse models and patients and then summarized arguments for and against possible involvement of wild-type SOD1 in non-SOD1 ALS as well as in SOD1-ALS.展开更多
基金This work was supported by Grants-in-Aid 16H04768 for Scientific Research(B)(to YF)and 19H05765 for Scientific Research on Innovative Areas(to YF)from the Ministry of Education,Culture,Sports,Science and Technology of Japan and also supported by the Pharmacological Research Foundation,Tokyo(to ET).
文摘Amyotrophic lateral sclerosis(ALS)is characterized by adult-onset progressive degeneration of upper and lower motor neurons.Increasing numbers of genes are found to be associated with ALS;among those,the first identified gene,SOD1 coding a Cu/Zn-superoxide dismutase protein(SOD1),has been regarded as the gold standard in the research on a pathomechanism of ALS.Abnormal accumulation of misfolded SOD1 in affected spinal motor neurons has been established as a pathological hallmark of ALS caused by mutations in SOD1(SOD1-ALS).Nonetheless,the involvement of wild-type SOD1 remains quite controversial in the pathology of ALS with no SOD1 mutations(non-SOD1 ALS),which occupies more than 90%of total ALS cases.In vitro studies have revealed post-translationally controlled misfolding and aggregation of wild-type as well as of mutant SOD1 proteins;therefore,SOD1 proteins could be a therapeutic target not only in SOD1-ALS but also in more prevailing cases,non-SOD1 ALS.In order to search for evidence on misfolding and aggregation of wild-type SOD1 in vivo,we reviewed pathological studies using mouse models and patients and then summarized arguments for and against possible involvement of wild-type SOD1 in non-SOD1 ALS as well as in SOD1-ALS.
