Mitochondrial dynamics underlie gene-environment interactions in Parkinson's

线粒体动力学是帕金森病基因与环境相互作用的基础

• 批准号: 8121815
• 负责人: Adrianne Chesser
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121815
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 1-Methyl-4-phenylpyridinium; Affect; Amino Acid Sequence; Animal Model; Antibodies; Calcineurin; Cell Count; Cell Culture Techniques; Cell Death; Cell Line; Cells; Cessation of life; Chimeric Proteins; Corpus striatum structure; Development; Disease; Dominant Genes; Dopamine; Environmental Exposure; Environmental Risk Factor; Etiology; Exhibits; Exposure to; Gene Combinations; Gene Mutation; Genes; Herbicides; High Pressure Liquid Chromatography; Human; In Vitro; Lead; Link; Mass Spectrum Analysis; Measures; Mediating; Meperidine; Mitochondria; Mitochondrial Proteins; Modeling; Morphology; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; PINK1 gene; Paraquat; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Peptide Sequence Determination; Play; Post-Translational Protein Processing; Predisposition; Proteins; Recessive Genes; Regulation; Research; Risk; Role; Secondary to; Signs and Symptoms; Substantia nigra structure; Symptoms; System; Toxic Environmental Substances; Toxic effect; Toxicant exposure; Transgenic Mice; Two-Dimensional Gel Electrophoresis; Western Blotting; base; cell injury; dopaminergic neuron; epidemiologic data; gene environment interaction; genetic risk factor; in vivo; interest; motor deficit; mutant; neurotoxicity; new therapeutic target; novel; novel therapeutics; overexpression; parkin gene/protein; programs; research study; toxicant; treatment strategy; ubiquitin-protein ligase; vector; vector control

DESCRIPTION (provided by applicant): The overall objective of the proposed project is to study the interaction between environmental and genetic risk factors in the development of Parkinson's disease (PD) with a focus on mechanisms of neurodegeneration. PD is the second most common neurodegenerative disease and is characterized by selective damage to dopaminergic neurons in the substantia nigra. This reduces dopamine levels in the striatum, and symptoms appear when striatal dopamine is decreased by 80%. The etiology of PD remains elusive, although exposure to various environmental toxicants is clearly implicated. In particular, the meperidine-derivative MPTP and the herbicide paraquat (PQ) have been linked to a long term risk of developing symptoms of PD. Additionally, familial forms of the disease have been characterized and a number of mutations, both autosomal dominant and recessive, have been identified. However, an interesting conundrum arose with the identification of patients who are heterozygous for known recessive mutations. Two of the most common genes yielding recessive mutations are parkin, an E3 ubiquitin ligase, and PINK1, a mitochondrial protein acting upstream of parkin. Mitochondrial dynamics represents a potential common pathway, as MPTP and PQ are known to affect mitochondrial activity, and PINK1 and parkin are involved with regulating mitochondrial morphology, key to appropriate mitochondrial function. The studies proposed in this application aim to explore in detail the potential interaction of environmental exposures and heterozygous expression of recessive mutations in PINK1 and parkin. Specifically, this research program aims to 1) Determine whether mice with recessive PD mutations exhibit enhanced nigrostriatal neurotoxicity following exposure to the environmental toxicants MPTP and PQ; 2) Determine if MPTP and PQ affect the expression of mitochondrial fission/fusion proteins in vivo and in vitro, and if this effect is accentuated by recessive mutations; and 3) Explore potential mechanisms mediating the effects of recessive PD mutations and environmental toxicants on mitochondrial fission/fusion proteins. These experiments will utilize both existing and novel animal models of recessive PD in conjunction with the environmental toxicants MPTP and PQ. Additionally, mechanisms of cell damage and mitochondrial dynamics will be assessed using a unique inducible cell culture model of recessive mutations. Careful analysis of fission and fusion proteins in the presence of the toxicants, mutant PINK1 and parkin, and the combination of genes and environmental toxicants will enhance understanding of PD pathogenesis. Finally, identification of other proteins involved in the regulation of mitochondrial dynamics will yield novel targets for the development of new therapeutic strategies. Thus, this research program will contribute greatly to our understanding of the pathogenesis of PD, the role of environmental exposures and the potential gene-environment interaction, providing opportunities for developing novel treatment strategies for this serious disease. PUBLIC HEALTH RELEVANCE: Parkinson's disease is the second leading cause of neurodegeneration, but improvements in treatment options are limited by a lack of understanding of the etiology of the disease. Environmental exposures and genetic mutations are both implicated, and this project aims to investigate the potential interaction between environmental toxicants and known recessive mutations. The experiments detailed here will provide further information regarding the pathogenesis of PD, allowing novel therapeutic strategies to be explored.

描述（由申请人提供）：拟议项目的总体目标是研究帕金森病（PD）发展中环境和遗传风险因素之间的相互作用，重点是神经退行性变的机制。 PD是第二常见的神经退行性疾病，其特征是黑质多巴胺能神经元的选择性损伤。这会降低纹状体中的多巴胺水平，当纹状体多巴胺减少 80% 时就会出现症状。尽管暴露于各种环境毒物显然与帕金森病的病因有关，但帕金森病的病因仍然难以捉摸。特别是，哌替啶衍生物 MPTP 和除草剂百草枯 (PQ) 与出现 PD 症状的长期风险有关。此外，该疾病的家族形式已得到表征，并且已鉴定出许多常染色体显性和隐性突变。然而，在识别已知隐性突变杂合的患者时出现了一个有趣的难题。产生隐性突变的两个最常见的基因是 Parkin（一种 E3 泛素连接酶）和 PINK1（一种作用于 Parkin 上游的线粒体蛋白）。线粒体动力学代表了一个潜在的共同途径，因为已知 MPTP 和 PQ 会影响线粒体活性，而 PINK1 和 Parkin 参与调节线粒体形态，这是适当线粒体功能的关键。本申请中提出的研究旨在详细探索环境暴露与 PINK1 和 Parkin 隐性突变杂合表达之间的潜在相互作用。具体而言，该研究计划旨在 1) 确定具有隐性 PD 突变的小鼠在暴露于环境毒物 MPTP 和 PQ 后是否表现出增强的黑质纹状体神经毒性； 2) 确定MPTP和PQ是否影响体内和体外线粒体裂变/融合蛋白的表达，以及这种影响是否因隐性突变而加剧； 3) 探索介导隐性PD突变和环境毒物对线粒体裂变/融合蛋白影响的潜在机制。这些实验将利用现有的和新型的隐性 PD 动物模型以及环境毒物 MPTP 和 PQ。此外，将使用独特的隐性突变诱导细胞培养模型评估细胞损伤和线粒体动力学机制。仔细分析毒物、突变体 PINK1 和 Parkin 存在下的裂变和融合蛋白，以及基因和环境毒物的组合将增强对 PD 发病机制的了解。最后，鉴定参与线粒体动力学调节的其他蛋白质将为开发新的治疗策略提供新的靶点。因此，该研究项目将极大地有助于我们了解帕金森病的发病机制、环境暴露的作用以及潜在的基因-环境相互作用，为开发这种严重疾病的新治疗策略提供机会。 公共卫生相关性：帕金森病是神经退行性疾病的第二大原因，但由于缺乏对该疾病病因的了解，治疗方案的改进受到限制。环境暴露和基因突变都涉及其中，该项目旨在研究环境毒物与已知隐性突变之间的潜在相互作用。这里详述的实验将提供有关 PD 发病机制的更多信息，从而探索新的治疗策略。