Quintanilla Rodrigo A, Jin Youngnam N, Fuenzalida Karen, Bronfman Miguel, Johnson Gail V W
Department of Anesthesiology, University of Rochester, Rochester, New York 14642.
Department of Pharmacology and Physiology, University of Rochester, Rochester, New York 14642-0002.
J Biol Chem. 2008 Sep 12;283(37):25628-25637. doi: 10.1074/jbc.M804291200. Epub 2008 Jul 18.
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.
过氧化物酶体增殖物激活受体γ（PPARγ）是转录因子PPAR家族的成员。合成的PPARγ激动剂被用作口服抗高血糖药物来治疗非胰岛素依赖型糖尿病。然而，新出现的证据表明，PPARγ激活剂也可以预防或减轻神经退行性变。基于这些先前的发现，本报告的重点是PPARγ激活在预防亨廷顿病（HD）线粒体功能丧失中的潜在神经保护作用。在这些研究中，我们使用了在生理水平表达野生型（STHdh(Q7/Q7)）或突变型（STHdh(Q111/Q111)）亨廷顿蛋白的纹状体细胞。用毒胡萝卜素处理突变细胞导致线粒体钙摄取显著减少、活性氧生成增加以及线粒体膜电位显著降低。罗格列酮激活PPARγ可预防突变纹状体细胞受到病理性钙增加挑战时发生的线粒体功能障碍和氧化应激。罗格列酮的有益作用可能是由PPARγ激活介导的，因为所有保护作用都被PPARγ拮抗剂GW9662阻断。此外，突变纹状体细胞中的PPARγ信号通路明显受损，PPARγ表达降低且PPARγ转录活性降低。用罗格列酮处理可增加线粒体质量水平，表明PPARγ通路在纹状体细胞线粒体功能中起作用。总之，这些证据表明罗格列酮激活PPARγ可减轻表达突变亨廷顿蛋白的纹状体细胞中的线粒体功能障碍，这可能是改善HD中发生的线粒体功能障碍的一条重要治疗途径。
