title: Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity.
abstract: 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.
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Song
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.forename: Alejandra
authors.initials: A
authors.lastname: Petrilli
authors.forename: Geraldine
authors.initials: G
authors.lastname: Liot
authors.forename: Eva
authors.initials: E
authors.lastname: Klinglmayr
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhou
authors.forename: Patrick
authors.initials: P
authors.lastname: Poquiz
authors.forename: Jonathan
authors.initials: J
authors.lastname: Tjong
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Pouladi
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Mark
authors.initials: M
authors.lastname: Ellisman
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rouiller
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarzenbacher
authors.forename: Blaise
authors.initials: B
authors.lastname: Bossy
authors.forename: Guy
authors.initials: G
authors.lastname: Perkins
authors.forename: Ella
authors.initials: E
authors.lastname: Bossy-Wetzel
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins