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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

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 | Huntingtin Protein | Mice | Microtubule-Associated Proteins | Mitochondria | Mitochondrial Proteins | Mutation | Nerve Tissue Proteins | Nuclear Proteins | Protein Binding

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Associated grants

  • Agency: NINDS NIH HHS, Id: R01 NS055193
  • Agency: NINDS NIH HHS, Id: R01NS055193
  • Agency: NEI NIH HHS, Id: R01 EY016164
  • Agency: NEI NIH HHS, Id: R01EY016164
  • Agency: NCRR NIH HHS, Id: P41 RR004050-21
  • Agency: NINDS NIH HHS, Id: R01 NS047456-05
  • Agency: NCRR NIH HHS, Id: P41 RR004050-24
  • Agency: Canadian Institutes of Health Research, Id: P41 RR004050
  • Agency: NCRR NIH HHS, Id: P41RR004050
  • Agency: NCRR NIH HHS, Id: R01 NS047456
  • Agency: NINDS NIH HHS, Id:

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