TRPC1, CALCIUM AND PARKINSON'S DISEASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 帕金森病(PD)是一种进行性神经退行性疾病，与黑质致密部多巴胺能神经元的选择性丢失有关。许多致病因素参与了黑质多巴胺能神经元的变性，包括自由基的产生、线粒体功能的损害、钙稳态的紊乱和细胞凋亡。这可能是一个共同的因素参与了帕金森病的发病机制。钙是上述所有过程中的一个共同因素，这可能是可能的联系。此外，钙稳态在刺激和抑制神经细胞死亡方面起着重要作用，钙离子介导了细胞凋亡。因此，依赖于空间和时间因素，钙通道可能对帕金森病等条件有有益的影响，在这种情况下，细胞凋亡可能是细胞死亡的最终模式。钙从两个来源进入细胞质；它要么从细胞内储存物中释放出来，要么通过质膜进入。细胞内钙离子的耗尽导致质膜钙通道的开放，这就是所谓的钙离子通道(SOCE)。最近，果蝇Trp基因的哺乳动物同源基因TRPC1被认为是SOCE通道。此外，我们最近的数据表明，经已知的引起PD的药物(MPP或沙龙醇)治疗后，TRPC1蛋白水平及其质膜定位显著降低。重要的是，TRPC1的过表达保护SH-SY5Y神经元细胞免受MPP和丹参素的细胞毒性。TRPC1的保护作用依赖于它的钙内流特性和促凋亡蛋白从内质网到线粒体的移位。这些数据首次证明，TRPC1具有保护多巴胺能神经元的作用。然而，TRPC1在体内的作用尚未阐明，TRPC1保护多巴胺能神经元的机制尚不清楚。因此，我们建议在动物模型(TRPC1基因敲除小鼠和PD小鼠模型)中扩展我们的知识，并通过确定TRPC1保护多巴胺能神经元的机制(S)来确定TRPC1在帕金森病中的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with selective loss of dopaminergic neurons in the substantia nigra pars compacta. A number of pathogenic factors have been implicated in the degeneration of dopaminergic neurons in the substantia nigra including generation of free radicals, impairment of mitochondrial function, disturbances of calcium homeostasis, and apoptosis. It could be hypothesized that a common factor should be involved in the pathogenesis of PD. Calcium being a common factor in all the above processes raises the possibility that this could be the possible link. Also calcium homeostasis plays an important role in stimulating and inhibiting neuronal cell death, and calcium mediates apoptosis. Thus, depending on spatial and temporal factors, calcium channels may have a salutary effect on conditions such as PD in which apoptosis may be the ultimate mode of cell death. Calcium enters the cytoplasm from two sources; it is either released from the intracellular stores, or it enters through the plasma membrane. Depletion of the intracellular stores leads to the opening of plasma membrane calcium channels which are known as store-operated calcium entry (SOCE) channels. Recently, a mammalian homologue of the Drosophila trp gene, TRPC1, has been suggested as a SOCE channel. Moreover, our recent data indicate that TRPC1 protein levels and its plasma membrane localization is significantly decreased after treatment with drugs known to cause PD (MPP+ or salsolinol). Importantly, overexpression of TRPC1 protected SH-SY5Y neuronal cells against the cellular toxicity elicited by MPP+ and salsolinol. The protection exhibited by TRPC1 was dependent on its calcium influx properties and the translocation of pro-apoptotic proteins from the endoplasmic reticulum to mitochondria. These data demonstrate, for the first time, that TRPC1 has a role in protecting dopaminergic neurons. Nevertheless, the role of TRPC1 in vivo has yet to be elucidated and the mechanisms by which TRPC1 protects dopaminergic neurons are not known. Thus, we propose to extend our knowledge in animal models (TRPC1 knockout mice, and PD mouse models) and determine the role of TRPC1 in PD by identifying mechanism(s) by which TRPC1 protects dopaminergic neurons.