PGC-1α at the intersection of bioenergetics regulation and neuron function: From Huntington's disease to Parkinson's disease and beyond

Neurons are specialized cells with unique features, including a constant high demand for energy. Mitochondria satisfy this constant demand, and are emerging as a central target for dysfunction in neurodegenerative disorders, such as Huntington's disease (HD) and Parkinson's disease. PPAR gamma co-activator-1 alpha a (PGC-1 alpha) is a transcription co-activator for nuclear receptors such as the PPARs, and thereby coordinates a number of gene expression programs to promote mitochondrial biogenesis and oxidative phosphorylation. Studies of PGC-1 alpha knock-out mice have yielded important insights into the role of PGC-1 alpha in normal nervous system function and potentially neurological disease. HD is caused by a polyglutamine repeat expansion in the huntingtin protein, and decades of work have established mitochondrial dysfunction as a key feature of HD pathogenesis. However, after the discovery of the HD gene, numerous reports produced strong evidence for altered transcription in HD. In 2006, a series of studies revealed that PGC-1 alpha transcription interference contributes to HD neurodegeneration, linking the nuclear transcriptionopathy with the mitochondrial dysfunction. Subsequent work has strengthened this view, and further extended the role of PGC-1 alpha within the CNS. Within the last year, studies of Parkinson's disease, another involuntary movement disorder long associated with mitochondrial dysfunction, have shown that PGC-1 alpha dysregulation is contributing to its pathogenesis. As PGC-1 alpha is likely also important for aging, a process with considerable relevance to neuron function, translational studies aimed at developing therapies based upon the PGC-1 alpha pathway as a high priority target are underway. (C) 2011 Elsevier Ltd. All rights reserved.