Document Detail


Mitochondrial redox signalling by p66Shc mediates ALS-like disease through Rac1 inactivation.
MedLine Citation:
PMID:  21828072     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-08-09
Journal Detail:
Title:  Human molecular genetics     Volume:  20     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-10-10     Completed Date:  2012-01-31     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  4196-208     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amyotrophic Lateral Sclerosis / enzymology*,  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,  metabolism*,  pathology
Mutant Proteins / toxicity
Mutation / genetics
Oxidation-Reduction / drug effects
Phenotype
Phosphorylation / drug effects
Phosphoserine / metabolism
Shc Signaling Adaptor Proteins / antagonists & inhibitors,  metabolism*
Signal Transduction* / drug effects
Superoxide Dismutase / metabolism
rac1 GTP-Binding Protein / metabolism*
Grant Support
ID/Acronym/Agency:
GGP09128//Telethon
Chemical
Reg. No./Substance:
0/Mutant Proteins; 0/SHC1 protein, human; 0/Shc Signaling Adaptor Proteins; 0/Shc1 protein, mouse; 17885-08-4/Phosphoserine; EC 1.15.1.1/Superoxide Dismutase; EC 3.6.5.2/rac1 GTP-Binding Protein

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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