Protein Aggregation and Neurotransmitter Deficits in Parkinson Disease

帕金森病中的蛋白质聚集和神经递质缺陷

• 批准号: 10656558
• 负责人: PAUL T KOTZBAUER
• 金额: $ 71.26万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656558
• 关键词: Address; Affect; Alzheimer' s disease related dementia; Amyloid beta-Protein; Attention; Autopsy; Basal Ganglia; Basal Nucleus of Meynert; Biological Assay; Biological Markers; Brain region; Carrier Proteins; Cell Nucleus; Cognition; Cognitive; Consent; Corpus striatum structure; Dementia; Deposition; Development; Enzyme-Linked Immunosorbent Assay; Freezing; Functional disorder; Gait; Goals; High Pressure Liquid Chromatography; Immunohistochemistry; Impaired cognition; Impairment; Individual; Lewy Bodies; Lewy Body Dementia; Longitudinal Studies; Longitudinal cohort; Measures; Memory; Methods; Neocortex; Nerve Degeneration; Neurons; Neurotransmitters; Outcome Measure; Parkinson Disease; Parkinson' s Dementia; Participant; Pathologic; Pathology; Patients; Pattern; Persons; Phenotype; Presynaptic Terminals; Proteins; Sampling; Substantia nigra structure; Thalamic structure; Therapeutic Trials; Time; Tissue Sample; Tissues; Visuospatial; abeta accumulation; alpha synuclein; brain tissue; cholinergic; cognitive function; cognitive impairment in Parkinson' s; dorsal raphe nucleus; executive function; improved; locus ceruleus structure; misfolded protein; motor symptom; neocortical; nerve supply; neurobehavioral; neuron loss; noradrenergic; novel strategies; postsynaptic; presynaptic; protein aggregation; protein biomarkers; tau Proteins; tau aggregation; therapeutic target; therapy development

Abstract People with Parkinson disease (PD) frequently develop dementia, which is associated with neocortical deposition of alpha-synuclein (α-syn) in Lewy bodies and referred to as Lewy body dementia (LBD), an Alzheimer’s Disease Related Dementia (ADRD). In addition, neuronal loss and deposition of aggregated α-syn also occurs in multiple subcortical nuclei including substantia nigra (dopaminergic), nucleus basalis of Meynert (cholinergic), locus coeruleus (noradrenergic) and dorsal raphe nuclei (serotonergic). Accumulation of α-syn likely contributes to degeneration of cortical neurons, which may also be affected by widespread Aβ accumulation that occurs in approximately 55% of PD with dementia cases and widespread tau accumulation in fewer cases. However, the affected subcortical nuclei project rostrally to thalamic, striatal, limbic and neocortical regions, and the loss of innervation from these nuclei also may contribute to cognitive impairment in PD. We developed postmortem tissue analysis methods to quantify pathologic accumulation of α-syn, Aβ and tau, neuronal degeneration marked by loss of synaptic terminals, and loss of innervating projections from dopaminergic, serotonergic, noradrenergic and cholinergic subcortical neurons. In this project we will collect autopsies from a longitudinal study of PD participants that measures cognition, neurobehavioral function and gait. We will sample cerebellar, basal ganglia, limbic and neocortical regions from frozen brain tissue for each autopsy case and analyze the tissue with the following goals: 1) Determine the relationship between α-syn, Aβ and tau accumulation, neuronal degeneration, and loss of subcortical projections. 2) Determine whether pathologic protein accumulation, neuronal degeneration and loss of projections from subcortical nuclei relate to global cognition and specific cognitive phenotypes, including impaired attention, memory, visuospatial and executive function. Defining the pathologic substrates for cognitive impairment in PD will provide further guidance for therapeutic targets, biomarkers, and outcome measures for therapeutic trials in PD.

摘要 帕金森病（PD）患者经常发生痴呆，这与新皮质 α-突触核蛋白（α-syn）沉积在路易体中，称为路易体痴呆（LBD）， 阿尔茨海默病相关性痴呆（ADRD）。此外，神经元的损失和聚集的α-syn的沉积 也发生在多个皮质下核，包括黑质（多巴胺能）、Meynert基底核 （胆碱能）、蓝斑（去甲肾上腺素能）和中缝背核（肾上腺素能）。α-syn蓄积 可能导致皮质神经元的变性，这也可能受到广泛的Aβ的影响。 在大约55%的PD痴呆病例中发生的tau蛋白蓄积和广泛的tau蛋白蓄积 在更少的情况下。然而，受影响的皮质下核团向丘脑、纹状体、边缘系统和丘脑投射。 新皮层区域，以及这些核的神经支配的丧失也可能导致认知障碍， 警局我们开发了死后组织分析方法来定量α-syn、Aβ和 tau蛋白，以突触末端丢失为标志的神经元变性，以及神经元的神经支配投射的丢失。 多巴胺能、多巴胺能、去甲肾上腺素能和胆碱能皮质下神经元。在这个项目中，我们将收集 从PD参与者的纵向研究中进行尸检，该研究测量认知、神经行为功能和 步态我们将从冷冻的脑组织中提取小脑、基底神经节、边缘系统和新皮层区域的样本， 目的：1）确定α-syn、Aβ、β-淀粉样蛋白（α-syn）、β-淀粉样蛋白（β-淀粉样蛋白）、β-淀粉样蛋白（β-淀粉样蛋白）、β-淀粉样蛋白（β-淀粉样蛋白）、β-淀粉样蛋白（β-淀粉样蛋白）之间的关系 以及tau积累、神经元变性和皮质下投射的丧失。2)确定是否 病理性蛋白质积累、神经元变性和皮质下核投射的丧失与 整体认知和特定认知表型，包括注意力、记忆力、视觉空间和 执行功能明确PD认知功能障碍的病理学基础，将为进一步研究PD认知功能障碍提供新的思路。 为PD治疗试验的治疗靶点、生物标志物和结局指标提供指导。