Transcriptional repression of PGC-α by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration

Huntington's disease (HID) is an inherited neurodegenerative disease caused by a glutamine repeat expansion in huntingtin protein. Transcriptional deregulation and altered energy metabolism have been implicated in HID pathogenesis. We report here that mutant huntingtin causes disruption of mitochondrial function by inhibiting expression of PGC-1 alpha, a transcriptional coactivator that regulates several metabolic processes, including mitochondrial biogenesis and respiration. Mutant huntingtin represses PGC-1 alpha gene transcription by associating with the promoter and interfering with the CREB/TAF4-dependent transcriptional pathway critical for the regulation of PGC-1 alpha gene expression. Crossbreeding of PGC-1 alpha knockout (KO) mice with HID knockin (KI) mice leads to increased neurodegeneration of striatal neurons and motor abnormalities in the HID mice. Importantly, expression of PGC-1 alpha partially reverses the toxic effects of mutant huntingtin in cultured striatal neurons. Moreover, lentiviral-mediated delivery of PGC-1 alpha in the striatum provides neuroprotection in the transgenic HID mice. These studies suggest a key role for PGC-1 alpha in the control of energy metabolism in the early stages of HID pathogenesis.