Endoplasmic Reticulum Stress and Parkinson's Disease

内质网应激与帕金森病

• 批准号: 6479891
• 负责人: DAVID RON
• 金额: $ 21.03万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6479891
• 关键词: 6 hydroxydopamine; CHO cells; Caenorhabditis elegans; PC12 cells; Parkinson's disease; SDS polyacrylamide gel electrophoresis; apoptosis; biological signal transduction; disulfide bond; endoplasmic reticulum; free radical oxygen; gene expression; gene mutation; glycosylation; immunocytochemistry; immunoprecipitation; laboratory mouse; mitochondria; neurons; neurotoxins; oxidative stress; protein degradation; protein folding; protein signal sequence; protein structure function

DESCRIPTION (provided by applicant) Recent observations suggest that abnormal conformations of proteins that are normal constituents of the dopaminergic neuron participate in death of this cell type in Parkinson Disease (PD). Some rare forms of PD can be linked to mutations that cause such proteotoxicity, either directly by affecting the primary structure of the protein converting it to a proteotoxin (e.g. a-SYN mutations) or indirectly, by affecting cellular processes that impact on the accumulation of proteotoxins (e.g. PARK2 mutations). However, such mutations are found in only a small fraction of PD patients, raising the question of how proteotoxicity is triggered in other cases. Recent experiments from our lab indicate that 6-hydroxydopamine and Rotenone, toxins implicated in experimental and environmental PD, cause an imbalance between the folding capacity of the endoplasmic reticulum (ER) and the load of client proteins placed on that organelle (so called ER stress). Uncompensated ER stress can promote proteotoxicity by competing for limited capacity of the ubiquitin proteasomal system and by producing ROS that can alter protein structure. Neurons are naturally prone to ER stress because of their extensive secretory activity and because of their highly elaborate membrane enclosed processes, which must be maintained by high rates of ER trafficking of client proteins. ER stress is normally counteracted by the unfolded protein response (UPR), an adaptive cellular signaling pathway that is activated specifically by ER stress. Impaired UPR signaling sensitizes cells specifically to the effect of ER stress. Therefore, we propose to test the role of ER stress in the development of PD by examining the effect of mutations that impair signaling in the UPR on an established model of experimental PD and on a component of genetic PD. We will determine if in mice lacking the key UPR gene, PERK dopaminergic neurons are hypersensitive to 6-hydroxydopamine. We will seek to identify the defect in ER function imparted by 6-hydroxydopamine and relate it, if possible, to the known ability of the toxin to inhibit mitochondrial complex-1. Finally, we will critically examine PARK2's role in ER-associated degradation of proteins. If the proposed experiments support a role for ER stress in the development of PD, this will effect a paradigmatic shift in our thinking about the pathogenesis of this common disorder.

描述（由申请人提供） 最近的观察结果表明，蛋白质的异常构象 多巴胺能神经元的正常成分参与了死亡 帕金森病（PD）的细胞类型。一些罕见形式的PD可以链接到 引起这种蛋白质毒性的突变，要么直接通过影响 将其转化为蛋白毒素的蛋白质的主要结构（例如A-Syn 突变）或间接影响影响对范围的细胞过程 蛋白质毒素的积累（例如PARK2突变）。但是，这种突变 仅在一小部分PD患者中发现，提出了一个问题 在其他情况下会触发蛋白毒性。我们实验室的最新实验 表明6-羟基多巴胺和烤罗烯酮，毒素与实验有关 和环境PD，导致折叠能力之间的不平衡 内质网（ER）和将客户蛋白的负载放在上面 细胞器（所谓的ER应力）。无补偿的ER应力可以促进 蛋白毒性通过竞争泛素蛋白酶体的有限容量来竞争 系统并通过产生可以改变蛋白质结构的ROS。神经元是 由于其广泛的分泌活动和 由于它们高度详尽的膜封闭过程，必须是 通过高率贩运客户蛋白的速率维持。 ER应力是 通常由展开的蛋白质反应（UPR）抵消，一种自适应 由ER应力专门激活的细胞信号通路。 损害UPR信号传导使细胞专门针对ER的效果敏感 压力。因此，我们建议测试ER应力在开发中的作用 通过检查损害UPR中信号传导的突变的效果，通过PD的效果 实验性PD的建立模型和遗传PD的成分。我们 将确定在缺乏关键UPR基因的小鼠中，PERK多巴胺能神经元 对6-羟基多巴胺高度敏感。我们将寻求确定 ER功能由6-羟基多巴胺赋予，并在可能的情况下将其与 毒素抑制线粒体复合物1的已知能力。最后，我们会的 批判性地检查了PARK2在蛋白质相关降解中的作用。如果 提出的实验支持ER应力在PD发展中的作用 这将影响我们对 这种常见的疾病。