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: 10522079
• 负责人: PAUL T KOTZBAUER
• 金额: $ 74.27万
• 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/10522079
• 关键词: Address; Affect; Alzheimer' s disease related dementia; Amyloid beta-Protein; Attention; Autopsy; Basal Ganglia; Basal Nucleus of Meynert; Biological Assay; Brain region; Carrier Proteins; Cell Nucleus; Cognition; Cognitive; Consent; Corpus striatum structure; Dementia; Deposition; 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; 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 development; cognitive function; cognitive impairment in Parkinson' s; disorder control; 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; targeted biomarker; 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)患者常患痴呆症，与新皮质相关 α-突触核蛋白(α-SYN)在路易体中的沉积，被称为路易体痴呆 阿尔茨海默病相关痴呆(ADRD)。此外，聚集的α-SYN的神经元丢失和沉积 也见于多个皮质下核，包括黑质(多巴胺能)、Meynert基底核 蓝斑(去甲肾上腺素能)和中缝背核(5-羟色胺能)。α-SYN的累积 可能导致皮质神经元退化，这也可能受到广泛传播的Aβ的影响 约55%的帕金森病痴呆患者出现蓄积，并广泛蓄积tau 在更少的情况下。然而，受影响的皮质下核团向丘脑、纹状体、边缘和 新皮质区域，以及这些核团神经支配的丧失也可能导致认知障碍。 警察。我们开发了死后组织分析方法来量化α-SYN、Aβ和 Tau，以突触终末丢失和神经投射丢失为特征的神经元变性 多巴胺能、5-羟色胺能、去甲肾上腺素和胆碱能皮质下神经元。在这个项目中，我们将收集 对帕金森病参与者进行的一项纵向研究的尸检结果，该研究测量了认知、神经行为功能和 步态。我们将从冰冻的脑组织中分别采集小脑、基底节、边缘和新皮质区域的样本。 1)确定α-SYN与A-β之间的关系 Tau堆积、神经元变性和皮质下投射丢失。2)确定是否 病理性蛋白堆积、神经元变性和皮质下核团投射丢失与 全球认知和特定认知表型，包括注意力、记忆力、视觉空间和 执行职能。明确帕金森病认知障碍的病理基础将提供进一步的 帕金森病治疗试验的治疗靶点、生物标记物和结果测量指南。