Mitochondrial redox signalling by p66Shc mediates ALS-like disease through Rac1 inactivation

Hum Mol Genet. 2011 Nov 1;20(21):4196-208. doi: 10.1093/hmg/ddr347. Epub 2011 Aug 9.


Increased oxidative stress and mitochondrial damage are among the mechanisms whereby mutant SOD1 (mutSOD1) associated with familial forms of amyotrophic lateral sclerosis (ALS) induces motoneuronal death. The 66 kDa isoform of the growth factor adapter Shc (p66Shc) is known to be central in the control of mitochondria-dependent oxidative balance. Here we report that expression of mutSOD1s induces the activation of p66Shc in neuronal cells and that the overexpression of inactive p66Shc mutants protects cells from mutSOD1-induced mitochondrial damage. Most importantly, deletion of p66Shc ameliorates mitochondrial function, delays onset, improves motor performance and prolongs survival in transgenic mice modelling ALS. We also show that p66Shc activation by mutSOD1 causes a strong decrease in the activity of the small GTPase Rac1 through a redox-sensitive regulation. Our results provide new insight into the potential mechanisms of mutSOD1-mediated mitochondrial dysfunction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / enzymology*
  • Amyotrophic Lateral Sclerosis / pathology*
  • Animals
  • Apoptosis / drug effects
  • Cytoprotection / drug effects
  • Down-Regulation / drug effects
  • Enzyme Activation / drug effects
  • Gene Deletion
  • Genes, Dominant / genetics
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Mutant Proteins / toxicity
  • Mutation / genetics
  • Oxidation-Reduction / drug effects
  • Phenotype
  • Phosphorylation / drug effects
  • Phosphoserine / metabolism
  • Shc Signaling Adaptor Proteins / antagonists & inhibitors
  • Shc Signaling Adaptor Proteins / metabolism*
  • Signal Transduction* / drug effects
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Superoxide Dismutase / metabolism
  • rac1 GTP-Binding Protein / metabolism*


  • Mutant Proteins
  • SHC1 protein, human
  • Shc Signaling Adaptor Proteins
  • Shc1 protein, mouse
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Phosphoserine
  • Superoxide Dismutase
  • rac1 GTP-Binding Protein