title: The interrelationship between mitochondrial dysfunction and transcriptional dysregulation in Huntington disease.
abstract: Huntington disease (HD) is an inherited neurodegenerative disease caused by an abnormal expansion of the CAG repeat region in the huntingtin (Htt) gene. Although the pathogenic mechanisms by which mutant Htt (mHtt) causes HD have not been fully elucidated, it is becoming increasingly apparent that mHtt can impair mitochondrial function directly, as well as indirectly by dysregulation of transcriptional processes. mHtt causes increased sensitivity to Ca(2+)-induced decreases in state 3 respiration and mitochondrial permeability transition pore (mPTP) opening concurrent with a reduction in mitochondrial Ca(2+) uptake capacity. Treatment of striatal cells expressing mHtt with thapsigargin results in a decrease in mitochondrial Ca(2+) uptake and membrane potential and an increase in reactive oxygen species (ROS) production. Transcriptional processes regulated by peroxisome proliferator-activated receptor gamma (PPAR gamma) coactivator-1 alpha (PGC-1 alpha), which are critical for mitochondrial biogenesis, have been shown to be impaired in HD. In addition, the PPAR gamma signaling pathway is impaired by mHtt and the activation of this pathway ameliorates many of the mitochondrial deficits, suggesting that PPAR gamma agonists may represent an important treatment strategy for HD.
authors.affiliation: Department of Anesthesiology, University of Rochester, 601 Elmwood Ave, Box 604, Rochester, NY 14642, USA.
authors.forename: Youngnam N
authors.initials: YN
authors.lastname: Jin
authors.forename: Gail V W
authors.initials: GV
authors.lastname: Johnson
mesh_terms: D002118:Calcium / Q000378:metabolism; D019069:Cell Respiration; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D050505:Mutant Proteins; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D006360:Heat-Shock Proteins; D050505:Mutant Proteins; D047495:PPAR gamma; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D002118:Calcium