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

Maria Grazia Pesaresi, Ilaria Amori, Carlotta Giorgi, Alberto Ferri, Paolo Fiorenzo, Francesca Gabanella, Anna Maria Salvatore, Marco Giorgio, Pier Giuseppe Pelicci, Paolo Pinton, Maria Teresa Carrì, Mauro Cozzolino

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article numberddr347
Pages (from-to)4196-4208
Number of pages13
JournalHuman Molecular Genetics
Issue number21
Publication statusPublished - Nov 2011

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology


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