Project I "Mechanisms of Pathological aSyn Transmission"

项目一“病理性非同步传播机制”

• 批准号: 10020334
• 负责人: VIRGINIA M LEE
• 金额: $ 52.07万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020334
• 关键词: Adopted; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Biochemical; Biological; Biophysics; Brain; Brain Diseases; Brain region; Cells; Characteristics; Clinical; Cognitive deficits; Corpus striatum structure; Cytoplasmic Inclusion; Data; Dementia; Disease; Environment; Grant; Heterogeneity; Human; In Vitro; Injections; Laboratories; Lewy Bodies; Lewy Body Dementia; Lewy Body Disease; Lewy neurites; Link; Modeling; Modification; Molecular; Molecular Conformation; Molecular Profiling; Multiple System Atrophy; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Oligodendroglia; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Pennsylvania; Play; Post-Translational Protein Processing; Proteins; Rattus; Recombinants; Research; Research Personnel; Role; Seeds; Senile Plaques; Specificity; Structure; Substantia nigra structure; Testing; Universities; Virginia; Wild Type Mouse; alpha synuclein; cell type; cerebral atrophy; comorbidity; connectome; dopaminergic neuron; improved; medical schools; motor impairment; mouse model; mouse synuclein alpha; neuron loss; neuropathology; nonhuman primate; novel; pars compacta; synucleinopathy; tau Proteins; trafficking; transmission process; uptake

PROJECT I: “Pathological α-Synuclein Transmission and Strains” PROJECT LEADER: VIRGINIA M.-Y. LEE Project I Summary/Abstract Project I, formerly Project III, is renumbered as Project I to improve the flow of the Projects in our re-submitted new U19 grant entitled “Center On Alpha-synuclein Strains In Alzheimer Disease & Related Dementias” at the University of Pennsylvania (Penn) Perelman School of Medicine (PSOM) to test the transmission and strain hypotheses of a-synucleinopathies. Dementia with Lewy bodies (DLB), Parkinson's disease (PD) without and with dementia (PDD), referred to here as Lewy body (LB) disorders (LBD), all share LB and Lewy neurite (LN) intra-neuronal pathology comprised of aggregated α-synuclein (aSyn). LBD, PDD and Alzheimer's disease (AD) with (AD+aSyn) or without LBs (AD-aSyn) are the most common aging related dementias. Moreover, LBD, AD+aSyn and multiple system atrophy (MSA), characterized by misfolded aSyn in glial cytoplasmic inclusions (GCIs), are the major neurodegenerative synucleinopathies. This diversity of clinical features and aSyn neuropathology in brains of neurodegenerative disease patients provides indirect support for the strain hypothesis wherein pathological aSyn adopts different conformations or strains that account for clinical and pathological heterogeneity between these disorders. Further, we propose the transmission hypothesis of aSyn strains to explain the variability in progression of LBD, AD+aSyn and MSA. However, both hypotheses need rigorous testing. Recently Project I and II investigators collaborated to demonstrate that intrastriatal injections of recombinant aSyn preformed fibrils (PFFs) into wildtype (WT) mice induced the templated misfolding and aggregation of endogenous aSyn that spread progressively across the striatal connectome to form PD-like LBs and LNs followed by dopaminergic (DA) neuron loss in the substantia nigra pars compacta (SNpc) and motor impairments characteristic of PD. Our key observations have been validated by many other laboratories and extended to rats and non-human primates (see preliminary non-human primate data in Project II) thereby supporting the transmission hypothesis. These confirmatory studies also showed that these novel models recapitulate LBD pathogenesis and will facilitate LBD research. We also have identified distinct aSyn strains with different conformations and biological activities through the serial in vitro propagation of synthetic aSyn PFFs generated from recombinant aSyn and we have isolated distinct human LBD, AD+aSyn and MSA aSyn strains from LBD and AD+aSyn, as well as MSA brains characterized genetically and neuropathologically by Core C from patients followed by Core B and studied clinically in Projects III and IV thereby collaboratively linking all U19 Projects and Cores. These studies defined distinct aSyn strains from AD+aSyn and LBD brains designated as aSyn-LB (LB+LN) and from MSA brains designated as aSyn-GCI. These and other preliminary data provide the framework for investigating pathogenic mechanisms of aSyn strain transmission in this new U19 Center application. To do this, we will use biochemical, biophysical and cell biological approaches to determine the molecular signatures of aSyn-LB and aSyn-GCI strains as well as identify the determinants of cell type specificities for each strain and elucidate mechanisms for templated propagation of these strains.

项目 I：“病理性 α-突触核蛋白传播和菌株” 项目负责人：弗吉尼亚·李 项目一总结/摘要 项目一（原项目三）被重新编号为项目一，以改善我们重新提交的项目流程 题为“阿尔茨海默病及相关痴呆症中的α-突触核蛋白菌株中心”的新 U19 资助，网址： 宾夕法尼亚大学 (Penn) 佩雷尔曼医学院 (PSOM) 测试传播和菌株 路易体痴呆（DLB）、无和帕金森病（PD）的假设。 痴呆症 (PDD)，此处称为路易体 (LB) 疾病 (LBD)，所有患者都有 LB 和路易体神经突 (LN) 神经元内病理包括聚集的 α-突触核蛋白 (aSyn)、PDD 和阿尔茨海默病 (AD)。 伴（AD+aSyn）或不伴LB（AD-aSyn）是最常见的衰老相关痴呆症。 AD+aSyn 和多系统萎缩 (MSA)，其特征是神经胶质细胞质内含物中错误折叠的 aSyn (GCI) 是主要的神经退行性突触核蛋白病，其临床特征和 aSyn 具有多样性。 神经退行性疾病患者大脑的神经病理学为该菌株提供了间接支持 假设病理性 aSyn 采用不同的构象或菌株来解释临床和 此外，我们提出了这些疾病之间的病理异质性。 aSyn 菌株解释了 LBD、AD+aSyn 和 MSA 进展的变异性。 最近，项目 I 和 II 的研究人员合作证明了纹状体内部的情况。 将重组aSyn预制原纤维（PFF）注射到野生型（WT）小鼠中诱导模板化 内源性 aSyn 的错误折叠和聚集逐渐扩散到纹状体连接组中 形成 PD 样 LB 和 LN，随后黑质致密部多巴胺能 (DA) 神经元丢失 （SNpc）和 PD 的运动障碍特征我们的主要观察结果已得到许多其他人的验证。 实验室并扩展到大鼠和非人类灵长类动物（参见项目中的初步非人类灵长类动物数据） II）从而支持了传播假说。这些验证性研究也表明这些小说。 模型概括了 LBD 发病机制，并将促进 LBD 研究。我们还发现了不同的 aSyn。 通过合成的体外连续繁殖，获得具有不同构象和生物活性的菌株 由重组 aSyn 产生的 aSyn PFF，我们分离出不同的人类 LBD、AD+aSyn 和 MSA 来自 LBD 和 AD+aSyn 的 aSyn 菌株，以及 MSA 大脑的遗传和神经病理学特征 由来自患者的核心 C 进行，随后是核心 B 并在项目 III 和 IV 中进行临床研究，从而合作进行 连接所有 U19 项目和核心。这些研究定义了来自 AD+aSyn 和 LBD 大脑的不同 aSyn 菌株。 指定为 aSyn-LB (LB+LN)，来自 MSA 的大脑指定为 aSyn-GCI 这些和其他初步的。 数据为研究这种新的 aSyn 菌株传播的致病机制提供了框架 为了做到这一点，我们将使用生物化学、生物物理和细胞生物学方法来实现这一点。 确定 aSyn-LB 和 aSyn-GCI 菌株的分子特征并确定细胞的决定因素 每种菌株的类型特异性并阐明这些菌株的模板化繁殖机制。