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

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.

Pubmed ID: 16636275


  • Deng HX
  • Shi Y
  • Furukawa Y
  • Zhai H
  • Fu R
  • Liu E
  • Gorrie GH
  • Khan MS
  • Hung WY
  • Bigio EH
  • Lukas T
  • Dal Canto MC
  • O'Halloran TV
  • Siddique T


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

May 2, 2006

Associated Grants

  • Agency: PHS HHS, Id: 54111
  • Agency: NINDS NIH HHS, Id: NS046535
  • Agency: NINDS NIH HHS, Id: NS050641
  • Agency: NINDS NIH HHS, Id: NS40308
  • Agency: NIGMS NIH HHS, Id: R01 GM054111

Mesh Terms

  • Amyotrophic Lateral Sclerosis
  • Animals
  • Humans
  • Mice
  • Mice, Transgenic
  • Mitochondria
  • Mutation
  • Phenotype
  • Protein Conformation
  • Spinal Cord
  • Superoxide Dismutase
  • Survival Rate