TRPC1, CALCIUM AND PARKINSON'S DISEASE

TRPC1、钙和帕金森病

• 批准号: 8360139
• 负责人: Brij B Singh
• 金额: $ 24.87万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2012-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360139
• 关键词: 1-Methyl-4-phenylpyridinium; Aftercare; Animal Model; Apoptosis; Calcium; Calcium Channel; Cell Death; Cell membrane; Cells; Cytoplasm; Data; Drosophila genus; Endoplasmic Reticulum; Exhibits; Free Radicals; Funding; Generations; Genes; Grant; Homeostasis; Homologous Gene; Impairment; Knockout Mice; Knowledge; Link; Mediating; Mitochondria; National Center for Research Resources; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenesis; Pharmaceutical Preparations; Play; Principal Investigator; Process; Property; Research; Research Infrastructure; Resources; Role; Signal Transduction; Source; Substantia nigra structure; TRPC1 protein; Time; Toxic effect; United States National Institutes of Health; cost; dopaminergic neuron; in vivo; mouse model; neuron loss; overexpression; pars compacta; pro-apoptotic protein; salsolinol

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 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丧失有关。 许多致病因素与黑质多巴胺能神经元的变性有关，包括自由基的产生、线粒体功能受损、钙稳态紊乱和细胞凋亡。 可以推测，PD 的发病机制中应该涉及一个共同因素。 钙是所有上述过程中的共同因素，这表明这可能是可能的联系。 钙稳态在刺激和抑制神经元细胞死亡中也起着重要作用，并且钙介导细胞凋亡。 因此，根据空间和时间因素，钙通道可能对帕金森病等疾病产生有益的影响，其中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释放，要么通过质膜进入。 细胞内储备的耗尽导致质膜钙通道的开放，这被称为储备操纵的钙进入（SOCE）通道。 最近，果蝇 trp 基因的哺乳动物同源物 TRPC1 被认为是 SOCE 通道。 此外，我们最近的数据表明，在使用已知导致 PD 的药物（MPP+ 或 Salsolinol）治疗后，TRPC1 蛋白水平及其质膜定位显着降低。 重要的是，TRPC1 的过度表达可以保护 SH-SY5Y 神经元细胞免受 MPP+ 和 Salsolinol 引起的细胞毒性。 TRPC1 表现出的保护作用取决于其钙流入特性以及促凋亡蛋白从内质网到线粒体的易位。 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，并且TRPC1保护多巴胺能神经元的机制尚不清楚。 因此，我们建议扩展我们对动物模型（TRPC1 敲除小鼠和 PD 小鼠模型）的了解，并通过确定 TRPC1 保护多巴胺能神经元的机制来确定 TRPC1 在 PD 中的作用。