Uncoupling protein 2 protects dopaminergic neurons from acute 1,2,3,6-methyl-phenyl-tetrahydropyridine toxicity
Uncoupling protein 2 protects dopaminergic neurons from acute 1,2,3,6-methyl-phenyl-tetrahydropyridine toxicity
复制标题
DOI：
10.1111/j.1471-4159.2005.03052.x
复制
发表时间：
2005-04-01
影响因子：
4.7
通讯作者：
Bartfai, T
中科院分区：
文献类型：
--
作者：
Conti, B;Sugama, S;Bartfai, T
氧化应激与散发性帕金森氏病的多巴胺能神经元的死亡有关。由于氧化应激可以由解偶联蛋白(UCPs)内源性调节，我们假设UCP2的特定神经元表达可以在帕金森病小鼠模型中发挥神经保护作用。UCP2是UCP家族的成员之一，在损伤后迅速在中枢神经系统诱导。在酪氨酸羟化酶启动子(TH-UCP2)的控制下，我们获得了在儿茶酚胺能神经元中高表达UCP2的转基因小鼠。在这些小鼠中，黑质的多巴胺能神经元显示UCP2的表达增加了两倍，线粒体解偶联增加，氧化应激指标显著减少，纹状体也观察到了这种影响。在急性暴露于1，2，3，6-甲基苯基-四氢吡啶后，TH-UCP2小鼠表现出神经保护和运动功能保留。我们的数据表明，UCP2可能是延缓帕金森病进展的药物靶点。
Oxidative stress is implicated in the death of dopaminergic neurons in sporadic forms of Parkinson's disease. Because oxidative stress can be modulated endogenously by uncoupling proteins (UCPs), we hypothesized that specific neuronal expression of UCP2, one member of the UCP family that is rapidly induced in the CNS following insults, could confer neuroprotection in a mouse model of Parkinson's disease. We generated transgenic mice overexpressing UCP2 in catecholaminergic neurons under the control of the tyrosine hydroxylase promoter (TH-UCP2). In these mice, dopaminergic neurons of the substantia nigra showed a twofold elevation in UCP2 expression, elevated uncoupling of their mitochondria, and a marked reduction in indicators of oxidative stress, an effect also observed in the striatum. Upon acute exposure to 1,2,3,6-methyl-phenyl-tetrahydropyridine, TH-UCP2 mice showed neuroprotection and retention of locomotor functions. Our data suggest that UCP2 may represent a drug target for slowing the progression of Parkinson's disease.