Rosiglitazone treatment prevents mitochondrial dysfunction in mutant huntingtin-expressing cells: possible role of peroxisome proliferator-activated receptor-gamma (PPARgamma) in the pathogenesis of Huntington disease.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the PPAR family of transcription factors. Synthetic PPARgamma agonists are used as oral anti-hyperglycemic drugs for the treatment of non-insulin-dependent diabetes. However, emerging evidence indicates that PPARgamma activators can also prevent or attenuate neurodegeneration. Given these previous findings, the focus of this report is on the potential neuroprotective role of PPARgamma activation in preventing the loss of mitochondrial function in Huntington disease (HD). For these studies we used striatal cells that express wild-type (STHdh(Q7/Q7)) or mutant (STHdh(Q111/Q111)) huntingtin protein at physiological levels. Treatment of mutant cells with thapsigargin resulted in a significant decrease in mitochondrial calcium uptake, an increase in reactive oxygen species production, and a significant decrease in mitochondrial membrane potential. PPARgamma activation by rosiglitazone prevented the mitochondrial dysfunction and oxidative stress that occurred when mutant striatal cells were challenged with pathological increases in calcium. The beneficial effects of rosiglitazone were likely mediated by activation of PPARgamma, as all protective effects were prevented by the PPARgamma antagonist GW9662. Additionally, the PPARgamma signaling pathway was significantly impaired in the mutant striatal cells with decreases in PPARgamma expression and reduced PPARgamma transcriptional activity. Treatment with rosiglitazone increased mitochondrial mass levels, suggesting a role for the PPARgamma pathway in mitochondrial function in striatal cells. Altogether, this evidence indicates that PPARgamma activation by rosiglitazone attenuates mitochondrial dysfunction in mutant huntingtin-expressing striatal cells, and this could be an important therapeutic avenue to ameliorate the mitochondrial dysfunction that occurs in HD.
Quintanilla
Rodrigo A
RA
Department of Anesthesiology, University of Rochester, Rochester, New York 14642.
Jin
Youngnam N
YN
Department of Pharmacology and Physiology, University of Rochester, Rochester, New York 14642-0002.
Fuenzalida
Karen
K
Centro de Regulación Celular y Patologia Joaquín V. Luco and Millennium Institute for Fundamental and Applied Biology, Department of Cellular and Molecular Biology, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 114-D, Chile.
Bronfman
Miguel
M
Centro de Regulación Celular y Patologia Joaquín V. Luco and Millennium Institute for Fundamental and Applied Biology, Department of Cellular and Molecular Biology, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 114-D, Chile.
Johnson
Gail V W
GVW
Department of Anesthesiology, University of Rochester, Rochester, New York 14642; Department of Pharmacology and Physiology, University of Rochester, Rochester, New York 14642-0002. Electronic address: gail_johnsonvoll@urmc.rochester.edu.
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008564:Membrane Potentials; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009687:Nuclear Proteins / Q000096:biosynthesis*; D047495:PPAR gamma / Q000378:metabolism*; D017382:Reactive Oxygen Species; D000077154:Rosiglitazone; D015398:Signal Transduction; D019284:Thapsigargin / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology*
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D007004:Hypoglycemic Agents; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D019284:Thapsigargin