title: Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1alpha in Huntington's disease neurodegeneration.
abstract: Huntington's disease (HD) is a fatal, dominantly inherited disorder caused by polyglutamine repeat expansion in the huntingtin (htt) gene. Here, we observe that HD mice develop hypothermia associated with impaired activation of brown adipose tissue (BAT). Although sympathetic stimulation of PPARgamma coactivator 1alpha (PGC-1alpha) was intact in BAT of HD mice, uncoupling protein 1 (UCP-1) induction was blunted. In cultured cells, expression of mutant htt suppressed UCP-1 promoter activity; this was reversed by PGC-1alpha expression. HD mice showed reduced food intake and increased energy expenditure, with dysfunctional BAT mitochondria. PGC-1alpha is a known regulator of mitochondrial function; here, we document reduced expression of PGC-1alpha target genes in HD patient and mouse striatum. Mitochondria of HD mouse brain show reduced oxygen consumption rates. Finally, HD striatal neurons expressing exogenous PGC-1alpha were resistant to 3-nitropropionic acid treatment. Altered PGC-1alpha function may thus link transcription dysregulation and mitochondrial dysfunction in HD.
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Weydt
authors.forename: Victor V
authors.initials: VV
authors.lastname: Pineda
authors.forename: Anne E
authors.initials: AE
authors.lastname: Torrence
authors.forename: Randell T
authors.initials: RT
authors.lastname: Libby
authors.forename: Terrence F
authors.initials: TF
authors.lastname: Satterfield
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Lazarowski
authors.forename: Merle L
authors.initials: ML
authors.lastname: Gilbert
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Morton
authors.forename: Theodor K
authors.initials: TK
authors.lastname: Bammler
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Strand
authors.forename: Libin
authors.initials: L
authors.lastname: Cui
authors.forename: Richard P
authors.initials: RP
authors.lastname: Beyer
authors.forename: Courtney N
authors.initials: CN
authors.lastname: Easley
authors.forename: Annette C
authors.initials: AC
authors.lastname: Smith
authors.forename: Dimitri
authors.initials: D
authors.lastname: Krainc
authors.forename: Serge
authors.initials: S
authors.lastname: Luquet
authors.forename: Ian R
authors.initials: IR
authors.lastname: Sweet
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schwartz
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
mesh_terms: D002001:Adipose Tissue, Brown / Q000503:physiopathology*; D000818:Animals; D001831:Body Temperature / Q000235:genetics; D001833:Body Temperature Regulation / Q000235:genetics*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006816:Huntington Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000502:physiology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors