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: 9321450
• 负责人: PAUL T KOTZBAUER
• 金额: $ 51.15万
• 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 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321450
• 关键词: Affect; Age; Amygdaloid structure; Amyloid beta-Protein; Attention; Autopsy; Basal Ganglia; Basal Nucleus of Meynert; Behavior; Biological Assay; Brain region; Carrier Proteins; Cell Nucleus; Cognition; Cognitive; Consent; Control Groups; Corpus striatum structure; Delusions; Dementia; Deposition; Dopamine; Enzyme-Linked Immunosorbent Assay; Freezing; Gait; Goals; Hallucinations; High Pressure Liquid Chromatography; Hippocampus (Brain); Histologic; Impaired cognition; Impairment; Individual; Inferior; Levodopa; Lewy Bodies; Lobule; Longitudinal Studies; Longitudinal cohort; Measurable; Measures; Memory; Methods; Middle frontal gyrus structure; Neurites; Neurologic; Neurons; Neurotransmitters; Norepinephrine; Outcome Measure; Parietal; Parkinson Disease; Participant; Pathologic; Pattern; Phenotype; Proteins; Sampling; Serotonin; Substantia nigra structure; System; Testing; Thalamic structure; Therapeutic Trials; Tissues; Visual; Visuospatial; abeta accumulation; acetylcholine transporter; alpha synuclein; association cortex; base; brain tissue; cholinergic; cognitive development; disorder control; dopamine transporter; dorsal raphe nucleus; executive function; improved; locus ceruleus structure; misfolded protein; neocortical; nerve supply; neurobehavioral; neuron loss; noradrenergic; novel; protein aggregation; putamen; serotonin transporter; tau Proteins; tau aggregation; therapeutic target; therapy development; therapy outcome

Abstract People with Parkinson disease (PD) frequently develop dementia, which is associated with neocortical deposition of alpha-synuclein (α-syn) in Lewy bodies and Lewy neurites. 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 impaired function of cortical neurons, which may also be affected by widespread Aβ accumulation that occurs in approximately 60% 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 accumulation of fibrillar α-syn, Aβ and tau, as well as the 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 cognitive, behavior, and gait function. We will sample thalamic, 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 deposition and the loss of dopaminergic, serotonergic, noradrenergic and cholinergic innervation. 2) Determine whether fibrillar protein deposition and loss of projections from subcortical nuclei relate to gait, global cognition and specific cognitive phenotypes, including: impaired attention, memory, visuospatial and executive function, fluctuations in attention, hallucinations and delusions. Defining the pathologic substrates for cognitive, behavior and gait impairment in PD will provide further guidance for therapeutic targets and outcome measures for therapeutic trials in PD.

抽象的 患有帕金森氏病（PD）的人经常发展痴呆症，这与新皮质有关 α-核蛋白（α-syn）在路易体体和路易神经上的沉积。此外，神经元损失和 聚集的α-syn的沉积也发生在多个皮层核中 （多巴胺能），Meynert（胆碱能）的巴萨利斯核（胆碱能），基因座（甲肾上腺素能）和背侧raphe 细胞核（血清素能）。 α-syn的积累可能导致皮质神经元功能受损，而皮质神经元的功能 也可能受到宽度Aβ积累的影响，该积累发生在大约60％的PD中 案例和宽度tau在更少的情况下积累。但是，受影响的皮层核项目 到丘脑，纹状体，边缘和新皮层区域，这些核神经的丧失也 可能导致PD认知障碍。我们开发了死后组织分析方法来量化 原纤维α-syn，Aβ和TAU的积累，以及多巴胺能支配项目的丧失， 血清素能，去甲肾上腺素能和胆碱能皮质神经元。在这个项目中，我们将从 测量认知，行为和步态功能的PD参与者的纵向研究。我们将采样 丘脑，小脑，基底神经节，边缘和新皮层区域，每次尸检 案例并以以下目标分析组织：1）确定α-Syn，Aβ和TAU之间的关系 沉积和多巴胺能，血清素能，去甲肾上腺素能和胆碱能神经的丧失。 2）确定 纤维蛋白的沉积和皮层核项目损失是否与步态相关，全球认知 以及特定的认知表型，包括：注意力受损，记忆，视觉和执行功能， 注意力，幻觉和妄想的波动。定义认知，行为的病理底物 并满足PD的损害将为治疗目标和结果指标提供进一步的指导 PD的治疗试验。