TY - JOUR
T1 - Mitochondrial redox signalling by p66Shc mediates ALS-like disease through Rac1 inactivation
AU - Pesaresi, Maria Grazia
AU - Amori, Ilaria
AU - Giorgi, Carlotta
AU - Ferri, Alberto
AU - Fiorenzo, Paolo
AU - Gabanella, Francesca
AU - Salvatore, Anna Maria
AU - Giorgio, Marco
AU - Pelicci, Pier Giuseppe
AU - Pinton, Paolo
AU - Carrì, Maria Teresa
AU - Cozzolino, Mauro
PY - 2011/11
Y1 - 2011/11
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddr347
DO - 10.1093/hmg/ddr347
M3 - Article
C2 - 21828072
AN - SCOPUS:80053959138
VL - 20
SP - 4196
EP - 4208
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 21
M1 - ddr347
ER -