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Truncated peroxisome proliferator-activated receptor-gamma coactivator 1alpha splice variant is severely altered in Huntington's disease.

Authors: Johri, A  Starkov, AA  Chandra, A  Hennessey, T  Sharma, A  Orobello, S  Squitieri, F  Yang, L  Beal, MF 
Citation: Johri A, etal., Neurodegener Dis. 2011;8(6):496-503. doi: 10.1159/000327910. Epub 2011 Jul 15.
Pubmed: (View Article at PubMed) PMID:21757867
DOI: Full-text: DOI:10.1159/000327910

BACKGROUND: Reduced peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC1alpha) 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 PGC1alpha protein undergoes posttranslational modifications that affect its transcriptional activity. The N-truncated splice variant of PGC1alpha (NT-PGC1alpha) is produced in tissues, but the role of truncated splice variants of PGC1alpha 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-PGC1alpha levels in HD. METHODS AND RESULTS: We found that the NT-PGC1alpha protein, a splice variant of approximately 38 kDa, but not full-length PGC1alpha is severely and consistently altered in human HD brain, human HD myoblasts, mouse HD models, and HD striatal cells. NT-PGC1alpha levels were significantly upregulated in HD cells and mouse brown fat by physiologically relevant stimuli that are known to upregulate PGC1alpha gene expression. This resulted in an increase in mitochondrial gene expression and cytochrome c content. CONCLUSION: Our data suggest that NT-PGC1alpha is an important component of the PGC1alpha transcriptional network, which plays a significant role in the pathogenesis of HD.


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RGD Object Information
RGD ID: 10395289
Created: 2015-08-28
Species: All species
Last Modified: 2015-08-28
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.