The Peptidyl-prolyl Isomerase Pin1 Up-regulation and Proapoptotic Function in Dopaminergic Neurons RELEVANCE TO THE PATHOGENESIS OF PARKINSON DISEASE
The Peptidyl-prolyl Isomerase Pin1 Up-regulation and Proapoptotic Function in Dopaminergic Neurons RELEVANCE TO THE PATHOGENESIS OF PARKINSON DISEASE
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DOI：
10.1074/jbc.m112.444224
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发表时间：
2013-07-26
影响因子：
4.8
通讯作者：
Kanthasamy, Anumantha G.
中科院分区：
文献类型：
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作者：
Ghosh, Anamitra;Saminathan, Hariharan;Kanthasamy, Anumantha G.
帕金森病(PD)是一种以黑质多巴胺能神经元缓慢进行性变性为特征的慢性神经退行性疾病。帕金森病的病理生理机制尚不清楚。Pin1是一种主要的肽基-脯氨酰异构酶，最近发现与某些疾病有关。值得注意的是，Ryo等人。(Ryo，A.，多哥，T.，Nakai，T.，Hirai，A.，Nishi，M.，Yamaguchi，A.，Suzuki，K.，Hirayasu，Y.，Kobayashi，H.，Perrem，K.，Liou，Y.C.，和Aoki，I.(2006)J.Biol.化学。281,4117-4125)提示Pin1参与帕金森病的病理过程。因此，我们试图通过细胞培养和动物模型系统地表征Pin1在帕金森病中的作用。令我们惊讶的是，我们观察到帕金森病毒物1-甲基-4-苯基吡啶(MPP+)处理的多巴胺能MN9D神经细胞以及1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)诱导的帕金森病小鼠模型黑质Pin1mRNA和蛋白水平显著上调。值得注意的是，PIN1在人类帕金森病脑的黑质中也有显著的表达，同时在多巴胺能神经元中也有很高的共定位。在功能研究中，siRNA介导的Pin1基因敲除几乎完全阻止了MPP+诱导的caspase-3激活和DNA片段化，表明Pin1具有促凋亡作用。有趣的是，包括胡桃仁酮在内的多种药物抑制了MPP+诱导的Pin1上调、突触核蛋白聚集、caspase-3激活和细胞死亡。此外，在PD的MPTP小鼠模型中，胡桃仁治疗抑制了Pin1的水平，并改善了运动障碍、多巴胺耗竭和黑质多巴胺能神经元的丢失。总之，我们的研究结果首次证明Pin1在帕金森病中上调，并在黑质纹状体多巴胺能系统中具有病理生理学作用，并提示调控Pin1水平可能是帕金森病的一种有用的翻译治疗策略。
Parkinson disease (PD) is a chronic neurodegenerative disease characterized by a slow and progressive degeneration of dopaminergic neurons in substantia nigra. The pathophysiological mechanisms underlying PD remain unclear. Pin1, a major peptidyl-prolyl isomerase, has recently been associated with certain diseases. Notably, Ryo et al. (Ryo, A., Togo, T., Nakai, T., Hirai, A., Nishi, M., Yamaguchi, A., Suzuki, K., Hirayasu, Y., Kobayashi, H., Perrem, K., Liou, Y. C., and Aoki, I. (2006) J. Biol. Chem. 281, 4117-4125) implicated Pin1 in PD pathology. Therefore, we sought to systematically characterize the role of Pin1 in PD using cell culture and animal models. To our surprise we observed a dramatic up-regulation of Pin1 mRNA and protein levels in dopaminergic MN9D neuronal cells treated with the parkinsonian toxicant 1-methyl-4-phenylpyridinium (MPP+) as well as in the substantia nigra of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. Notably, a marked expression of Pin1 was also observed in the substantia nigra of human PD brains along with a high co-localization of Pin1 within dopaminergic neurons. In functional studies, siRNA-mediated knockdown of Pin1 almost completely prevented MPP+-induced caspase-3 activation and DNA fragmentation, indicating that Pin1 plays a proapoptotic role. Interestingly, multiple pharmacological Pin1 inhibitors, including juglone, attenuated MPP+-induced Pin1 up-regulation, -synuclein aggregation, caspase-3 activation, and cell death. Furthermore, juglone treatment in the MPTP mouse model of PD suppressed Pin1 levels and improved locomotor deficits, dopamine depletion, and nigral dopaminergic neuronal loss. Collectively, our findings demonstrate for the first time that Pin1 is up-regulated in PD and has a pathophysiological role in the nigrostriatal dopaminergic system and suggest that modulation of Pin1 levels may be a useful translational therapeutic strategy in PD.