title: Truncated peroxisome proliferator-activated receptor-γ coactivator 1α splice variant is severely altered in Huntington's disease.
abstract: BACKGROUND
  Reduced peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) 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 PGC1α protein undergoes posttranslational modifications that affect its transcriptional activity. The N-truncated splice variant of PGC1α (NT-PGC1α) is produced in tissues, but the role of truncated splice variants of PGC1α 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-PGC1α levels in HD.
  
  
  RESULTS
  We found that the NT-PGC1α protein, a splice variant of ∼38 kDa, but not full-length PGC1α is severely and consistently altered in human HD brain, human HD myoblasts, mouse HD models, and HD striatal cells. NT-PGC1α levels were significantly upregulated in HD cells and mouse brown fat by physiologically relevant stimuli that are known to upregulate PGC1α gene expression. This resulted in an increase in mitochondrial gene expression and cytochrome c content.
  
  
  CONCLUSIONS
  Our data suggest that NT-PGC1α is an important component of the PGC1α transcriptional network, which plays a significant role in the pathogenesis of HD.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA. asj2002 @ med.cornell.edu
authors.forename: Ashu
authors.initials: A
authors.lastname: Johri
authors.forename: Anatoly A
authors.initials: AA
authors.lastname: Starkov
authors.forename: Abhishek
authors.initials: A
authors.lastname: Chandra
authors.forename: Thomas
authors.initials: T
authors.lastname: Hennessey
authors.forename: Abhijeet
authors.initials: A
authors.lastname: Sharma
authors.forename: Sara
authors.initials: S
authors.lastname: Orobello
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Squitieri
authors.forename: Lichuan
authors.initials: L
authors.lastname: Yang
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D000368:Aged; D000818:Animals; D015153:Blotting, Western; D001923:Brain Chemistry / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003080:Cold Temperature; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D006816:Huntington Disease / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D032446:Myoblasts / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020033:Protein Isoforms; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020033:Protein Isoforms; D014157:Transcription Factors; D000242:Cyclic AMP