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

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


  • Song W
  • Chen J
  • Petrilli A
  • Liot G
  • Klinglmayr E
  • Zhou Y
  • Poquiz P
  • Tjong J
  • Pouladi MA
  • Hayden MR
  • Masliah E
  • Ellisman M
  • Rouiller I
  • Schwarzenbacher R
  • Bossy B
  • Perkins G
  • Bossy-Wetzel E


Nature medicine

Publication Data

March 8, 2011

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:

Mesh Terms

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