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Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity.

Nature medicine | Mar 8, 2011

http://www.ncbi.nlm.nih.gov/pubmed/21336284

Huntington's disease is an inherited and incurable neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in huntingtin (encoded by HTT). PolyQ length determines disease onset and severity, with a longer expansion causing earlier onset. The mechanisms of mutant huntingtin-mediated neurotoxicity remain unclear; however, mitochondrial dysfunction is a key event in Huntington's disease pathogenesis. Here we tested whether mutant huntingtin impairs the mitochondrial fission-fusion balance and thereby causes neuronal injury. We show that mutant huntingtin triggers mitochondrial fragmentation in rat neurons and fibroblasts of individuals with Huntington's disease in vitro and in a mouse model of Huntington's disease in vivo before the presence of neurological deficits and huntingtin aggregates. Mutant huntingtin abnormally interacts with the mitochondrial fission GTPase dynamin-related protein-1 (DRP1) in mice and humans with Huntington's disease, which, in turn, stimulates its enzymatic activity. Mutant huntingtin-mediated mitochondrial fragmentation, defects in anterograde and retrograde mitochondrial transport and neuronal cell death are all rescued by reducing DRP1 GTPase activity with the dominant-negative DRP1 K38A mutant. Thus, DRP1 might represent a new therapeutic target to combat neurodegeneration in Huntington's disease.

Pubmed ID: 21336284 RIS Download

Mesh terms: Animals | Disease Models, Animal | GTP Phosphohydrolases | Humans | Mice | Microtubule-Associated Proteins | Mitochondria | Mitochondrial Proteins | Mutation | Nerve Tissue Proteins | Nuclear Proteins | Protein Binding

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Associated grants

  • Agency: NCRR NIH HHS, Id: P41 RR004050
  • Agency: NCRR NIH HHS, Id: P41 RR004050-21
  • Agency: NCRR NIH HHS, Id: P41 RR004050-24
  • Agency: NCRR NIH HHS, Id: P41RR004050
  • Agency: NINDS NIH HHS, Id: R01 NS047456
  • Agency: NINDS NIH HHS, Id: R01 NS047456-05
  • Agency: NEI NIH HHS, Id: R01EY016164
  • Agency: NINDS NIH HHS, Id: R01NS055193
  • Agency: Canadian Institutes of Health Research, Id:

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