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

First Author  Pesaresi MG Year  2011
Journal  Hum Mol Genet Volume  20
Issue  21 Pages  4196-208
PubMed ID  21828072 Mgi Jnum  J:176680
Mgi Id  MGI:5292431 Doi  10.1093/hmg/ddr347
Citation  Pesaresi MG, et al. (2011) Mitochondrial redox signalling by p66Shc mediates ALS-like disease through Rac1 inactivation. Hum Mol Genet 20(21):4196-208
abstractText  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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