Author/Editor		Cui, Libin; Jeong, Hyunkyung; Borovecki, Fran; Parkhurst, Christopher N; Tanese, Naoko; Krainc, Dimitri
Title		Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration
Type		članek
Source		Cell
Vol. and No.		Letnik 127, št. 1
Publication year		2006
Volume		str. 59-69
Language		eng
Abstract		Huntington's disease (HD) is an inherited neurodegenerative disease caused by a glutamine repeat expansion in huntingtin protein. Transcriptional deregulation and altered energy metabolism have been implicated in HD pathogenesis. We report here that mutant huntingtin causes disruption of mitochondrial function by inhibiting expression of PGC-1alpha, a transcriptional coactivator that regulates several metabolic processes, including mitochondrial biogenesis and respiration. Mutant huntingtin represses PGC-1alpha gene transcription by associating with the promoter and interfering with the CREB/TAF4-dependent transcriptional pathway critical for the regulation of PGC-1alpha gene expression. Crossbreeding of PGC-1alpha knockout (KO) mice with HD knockin (KI) mice leads to increased neurodegeneration of striatal neurons and motor abnormalities in the HD mice. Importantly, expression of PGC-1alpha partially reverses the toxic effects of mutant huntingtin in cultured striatal neurons. Moreover, lentiviral-mediated delivery of PGC-1alpha in the striatum provides neuroprotection in the transgenic HD mice. These studies suggest a key role for PGC-1alpha in the control of energy metabolism in the early stages of HD pathogenesis.
Descriptors		GENE EXPRESSION REGULATION NERVE TISSUE PROTEINS NUCLEAR PROTEINS TRANS-ACTIVATORS TRANSCRIPTION, GENETIC ANIMALS BEHAVIOR, ANIMAL CELLS, CULTURED CORPUS STRIATUM ENERGY METABOLISM GENETIC VECTORS LENTIVIRUS MICE MICE, KNOCKOUT MITOCHONDRIA NERVE DEGENERATION NEURONS