title: A role of mitochondrial complex II defects in genetic models of Huntington's disease expressing N-terminal fragments of mutant huntingtin.
abstract: Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of a CAG repeat encoding a polyglutamine tract in the huntingtin (Htt) protein. The mutation leads to neuronal death through mechanisms which are still unknown. One hypothesis is that mitochondrial defects may play a key role. In support of this, the activity of mitochondrial complex II (C-II) is preferentially reduced in the striatum of HD patients. Here, we studied C-II expression in different genetic models of HD expressing N-terminal fragments of mutant Htt (mHtt). Western blot analysis showed that the expression of the 30 kDa Iron-Sulfur (Ip) subunit of C-II was significantly reduced in the striatum of the R6/1 transgenic mice, while the levels of the FAD containing catalytic 70 kDa subunit (Fp) were not significantly changed. Blue native gel analysis showed that the assembly of C-II in mitochondria was altered early in N171-82Q transgenic mice. Early loco-regional reduction in C-II activity and Ip protein expression was also demonstrated in a rat model of HD using intrastriatal injection of lentiviral vectors encoding mHtt. Infection of the rat striatum with a lentiviral vector coding the C-II Ip or Fp subunits induced a significant overexpression of these proteins that led to significant neuroprotection of striatal neurons against mHtt neurotoxicity. These results obtained in vivo support the hypothesis that structural and functional alterations of C-II induced by mHtt may play a critical role in the degeneration of striatal neurons in HD and that mitochondrial-targeted therapies may be useful in its treatment.
authors.affiliation: The first two authors contributed equally to the present study.
authors.forename: Maria
authors.initials: M
authors.lastname: Damiano
authors.forename: Elsa
authors.initials: E
authors.lastname: Diguet
authors.forename: Carole
authors.initials: C
authors.lastname: Malgorn
authors.forename: Marilena
authors.initials: M
authors.lastname: D'Aurelio
authors.forename: Laurie
authors.initials: L
authors.lastname: Galvan
authors.forename: Fanny
authors.initials: F
authors.lastname: Petit
authors.forename: Lucile
authors.initials: L
authors.lastname: Benhaim
authors.forename: Martine
authors.initials: M
authors.lastname: Guillermier
authors.forename: Diane
authors.initials: D
authors.lastname: Houitte
authors.forename: Noelle
authors.initials: N
authors.lastname: Dufour
authors.forename: Philippe
authors.initials: P
authors.lastname: Hantraye
authors.forename: Josep M
authors.initials: JM
authors.lastname: Canals
authors.forename: Jordi
authors.initials: J
authors.lastname: Alberch
authors.forename: Thierry
authors.initials: T
authors.lastname: Delzescaux
authors.forename: Nicole
authors.initials: N
authors.lastname: Déglon
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Brouillet
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D042963:Electron Transport Complex II / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D024101:Mitochondrial Proteins; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D042963:Electron Transport Complex II