Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria

Han Xiang Deng, Yong Shi, Yoshiaki Furukawa, Hong Zhai, Ronggen Fu, Erdong Liu, George H. Gorrie, Mohammad S. Khan, Wu Yen Hung, Eileen H. Bigio, Thomas Lukas, Mauro C. Dal Canto, Thomas V. O'Halloran, Teepu Siddique

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316 引用 (Scopus)

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Twenty percent of the familial form of amyotrophic lateral sclerosis (ALS) is caused by mutations in the Cu, Zn-superoxide dismutase gene (SOD1) through the gain of a toxic function. The nature of this toxic function of mutant SOD1 has remained largely unknown. Here we show that WT SOD1 not only hastens onset of the ALS phenotype but can also convert an unaffected phenotype to an ALS phenotype in mutant SOD1 transgenic mouse models. Further analyses of the single- and double-transgenic mice revealed that conversion of mutant SOD1 from a soluble form to an aggregated and detergent-insoluble form was associated with development of the ALS phenotype in transgenic mice. Conversion of WT SOD1 from a soluble form to an aggregated and insoluble form also correlates with exacerbation of the disease or conversion to a disease phenotype in double-transgenic mice. This conversion, observed in the mitochondrial fraction of the spinal cord, involved formation of insoluble SOD1 dimers and multimers that are crosslinked through intermolecular disulfide bonds via oxidation of cysteine residues in SOD1. Our data thus show a molecular mechanism by which SOD1, an important protein in cellular defense against free radicals, is converted to aggregated and apparently ALS-associated toxic dimers and multimers by redox processes. These findings provide evidence of direct links among oxidation, protein aggregation, mitochondrial damage, and SOD1-mediated ALS, with possible applications to the aging process and other late-onset neurodegenerative disorders. Importantly, rational therapy based on these observations can now be developed and tested.

元の言語English
ページ(範囲)7142-7147
ページ数6
ジャーナルProceedings of the National Academy of Sciences of the United States of America
103
発行部数18
DOI
出版物ステータスPublished - 2006 5 2
外部発表Yes

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ASJC Scopus subject areas

  • Genetics
  • General

これを引用

Deng, H. X., Shi, Y., Furukawa, Y., Zhai, H., Fu, R., Liu, E., Gorrie, G. H., Khan, M. S., Hung, W. Y., Bigio, E. H., Lukas, T., Dal Canto, M. C., O'Halloran, T. V., & Siddique, T. (2006). Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria. Proceedings of the National Academy of Sciences of the United States of America, 103(18), 7142-7147. https://doi.org/10.1073/pnas.0602046103