NEUROFILAMENT INVOLVEMENT IN LEWY BODY DISORDERS

神经丝参与路易体疾病

• 批准号: 2271298
• 负责人: WILLIAM D HILL
• 金额: $ 8.96万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2271298
• 关键词: Alzheimer's disease; Chordata; Parkinson's disease; RNase protection assay; antibody; cellular pathology; epitope mapping; in situ hybridization; inclusion body; monoclonal antibody; nervous system disorder; neurofilament; neurofilament proteins; phosphorylation; posttranslational modifications; protein biosynthesis; protein isoforms; protein purification; proteolysis

Lewy bodies are filamentous inclusions that occur in selected brainstem, limbic, and neocortical neurons in several disabling and dementing neurodegenerative diseases, including Parkinson's disease, diffuse Lewy body disease, and a subset of Alzheimer's disease. Neither the pathogenic events leading to Lewy body formation, nor the composition of Lewy bodies are known. The long-term objectives of this research are to identify the key components of Lewy bodies, to characterize both immediate pathogenic events leading to the formation of Lewy bodies as well as earlier or more primary pathological events and to clarify the relationship between Alzheimer's disease and Lewy body associated disorders. In this proposal a limited set of goals will be pursued that focus on the role of the neurofilament triplet proteins in the formation of Lewy body filaments and on their role as a target in the pathogenesis of these disorders. Neurofilament proteins are the focus of the application because they are currently the most convincing and consistent of the potential Lewy body filament molecules. The overall hypothesis of this application is that neurofilament metabolism is disrupted in Lewy body associated disorders such as Parkinson's disease, diffuse Lewy body disease, and subsets of Alzheimer's disease. The specific aims center on neurofilament involvement in these Lewy body associated diseases. These aims incorporate analysis of neurofilament metabolism in vulnerable neuron populations at the level of mRNA and protein expression, including post-translational modifications to neurofilament subunits. To accomplish this epitope mapping will be employed with a unique library of antibodies combined with confocal microscopy, quantitative in situ hybridization and ribonuclease protection assays. The specific aims also incorporate the isolation and characterization of Lewy bodies in order to directly determine if neurofilament subunits are components and if they are post-translationally modified. Novel strategies will be used for the isolation of Lewy bodies (affinity based) and the production of Lewy body specific antibodies (tolerization based). Additionally, this information will be compared between cortical and subcortical neuronal populations as well as across disease categories. While neurofilaments have been strongly implicated in the formation of Lewy body filaments, and alterations in neurofilament processing are suspected in Lewy body associated disorders, the question of their involvement has not been settled. The intention of this proposal is to move towards a clearer assessment of the role of neurofilaments in these disorders.

路易的身体是丝状夹杂物，在选定的脑干中发生， 多种残疾和痴呆中的边缘和新皮质神经元 神经退行性疾病，包括帕金森氏病，分散的路易 身体疾病，以及阿尔茨海默氏病的子集。病原体都不是 导致Lewy身体形成的事件，也没有Lewy Bodies的组成 已知。 这项研究的长期目标是确定关键 路易体的组成部分，以表征两种立即致病性 导致路易尸体以及更早或更早的事件 主要的病理事件并阐明 阿尔茨海默氏病和路易相关的疾病。在此提案中 将追求有限的目标，专注于 神经丝三胞胎蛋白在路易体丝形成中 关于他们作为这些疾病发病机理的目标的作用。 神经丝蛋白是应用的重点，因为它们是 目前，潜在的Lewy身体最有说服力和一致 细丝分子。 该应用的总体假设是神经丝 Lewy身体相关疾病（例如） 帕金森氏病，弥漫性路易人身体疾病和阿尔茨海默氏症的子集 疾病。特定的目的是神经丝参与其中的中心 路易相关的疾病。这些目的包括对 在弱势神经元种群中的神经丝代谢 mRNA和蛋白质表达，包括翻译后修饰 神经丝亚基。完成此表位映射将是 由独特的抗体库与共聚焦相结合 显微镜，定量原位杂交和核糖核酸酶保护 测定。具体目的还包括隔离和 路易尸体的表征，以直接确定是否 神经丝亚基是组件，如果它们是后翻译的 修改的。新型策略将用于隔离路易尸体 （基于亲和力）和Lewy身体特异性抗体的产生 （基于公差）。此外，将比较此信息 皮质和皮质下神经元种群以及跨越之间 疾病类别。 尽管神经丝与形成很大 Lewy身体丝和神经丝处理的改变是 怀疑在路易相关的疾病中，他们的问题 参与尚未解决。该提议的目的是 朝着更清楚地评估神经丝中的作用 疾病。