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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 帕金森病（Parkinson's disease，PD）是一种进行性的神经退行性疾病，与黑质多巴胺能神经元的选择性丢失有关。 黑质多巴胺能神经元的变性与许多致病因素有关，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。 可以推测PD的发病机制中有一个共同的因素。 钙是所有上述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元细胞死亡中起重要作用，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PD等疾病有有益的影响，其中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。 细胞内钙库的消耗导致质膜钙通道的开放，这被称为钙库操纵的钙进入（SOCE）通道。 最近，果蝇trp基因的哺乳动物同源物TRPC 1被认为是SOCE通道。 此外，我们最近的数据表明，TRPC 1蛋白水平及其质膜定位在用已知引起PD的药物（MPP+或salsolinol）治疗后显著降低。 重要的是，TRPC 1的过表达保护SH-SY 5 Y神经元细胞免受MPP+和salsolinol引起的细胞毒性。 TRPC 1所表现出的保护作用依赖于其钙内流特性和促凋亡蛋白从内质网到线粒体的转运。 这些数据首次证明TRPC 1具有保护多巴胺能神经元的作用。 然而，TRPC 1在体内的作用尚未阐明，TRPC 1保护多巴胺能神经元的机制也不清楚。 因此，我们建议在动物模型（TRPC 1敲除小鼠和PD小鼠模型）中扩展我们的知识，并通过识别TRPC 1保护多巴胺能神经元的机制来确定TRPC 1在PD中的作用。