Author/Editor		Weydt, Patrick; Pineda, Victor V; Torrence, Anne E; Libby, Randell T; Satterfield, Terence F; Krainc, Dimitri
Title		Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1alpha in Huntington's disease neurodegeneration
Type		članek
Source		Cell Metab
Vol. and No.		Letnik 4, št. 5
Publication year		2006
Volume		str. 349-62
Language		eng
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.
Descriptors		ANIMALS BODY TEMPERATURE BODY TEMPERATURE REGULATION CELLS, CULTURED DISEASE MODELS, ANIMAL HEAT-SHOCK PROTEINS MICE MICE, TRANSGENIC MITOCHONDRIA SIGNAL TRANSDUCTION TRANSCRIPTION FACTORS TRANSCRIPTION, GENETIC