Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1alpha in Huntington's disease neurodegeneration.
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.
Weydt
Patrick
P
Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA.
Pineda
Victor V
VV
Torrence
Anne E
AE
Libby
Randell T
RT
Satterfield
Terrence F
TF
Lazarowski
Eduardo R
ER
Gilbert
Merle L
ML
Morton
Gregory J
GJ
Bammler
Theodor K
TK
Strand
Andrew D
AD
Cui
Libin
L
Beyer
Richard P
RP
Easley
Courtney N
CN
Smith
Annette C
AC
Krainc
Dimitri
D
Luquet
Serge
S
Sweet
Ian R
IR
Schwartz
Michael W
MW
La Spada
Albert R
AR
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
D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors