Truncated Peroxisome Proliferator-Activated Receptor-γ Coactivator 1α Splice Variant Is Severely Altered in Huntington's Disease

Background: Reduced peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1 alpha) gene expression has been observed in striatal cell lines, transgenic mouse models of Huntington's disease (HD), and brain tissue from HD patients. As this protein is a key transcription regulator of the expression of many mitochondrial proteins, these observations strongly support the role of aberrant mitochondrial function in the pathogenesis of HD. The PGC1 alpha protein undergoes posttranslational modifications that affect its transcriptional activity. The N-truncated splice variant of PGC1 alpha (NT-PGC1 alpha) is produced in tissues, but the role of truncated splice variants of PGC1 alpha in HD and in the regulation of mitochondrial gene expression has not been elucidated. Objective: To examine the expression and modulation of expression of NT-PGC1 alpha levels in HD. Methods and Results: We found that the NT-PGC1 alpha protein, a splice variant of similar to 38 kDa, but not full-length PGC1 alpha is severely and consistently altered in human HD brain, human HD myoblasts, mouse HD models, and HD striatal cells. NT-PGC1 alpha levels were significantly upregulated in HD cells and mouse brown fat by physiologically relevant stimuli that are known to upregulate PGC1 alpha gene expression. This resulted in an increase in mitochondrial gene expression and cytochrome c content. Conclusion: Our data suggest that NT-PGC1 alpha is an important component of the PGC1 alpha transcriptional network, which plays a significant role in the pathogenesis of HD. Copyright (C) 2011 S. Karger AG, Basel