Project I "Mechanisms of Pathological aSyn Transmission"

项目一“病理性非同步传播机制”

• 批准号: 10373920
• 负责人: VIRGINIA M LEE
• 金额: $ 45.27万
• 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/10373920
• 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; Dementia with Lewy Bodies; Disease; Environment; Grant; Heterogeneity; Human; In Vitro; Injections; Laboratories; Lewy Bodies; 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-突触核蛋白传递和菌株” 项目负责人：弗吉尼亚M.- Y.李 项目I摘要/摘要 项目一，原项目三，重新编号为项目一，以改善我们重新提交的项目清单中的项目流程。 新的U19赠款题为“中心阿尔法突触核蛋白菌株在阿尔茨海默病和相关痴呆症”， 宾夕法尼亚大学（Penn）佩雷尔曼医学院（PSOM）测试传播和菌株 a-突触核蛋白病的假说。路易体痴呆（DLB），帕金森病（PD）， 患有痴呆症（PDD）的人，在这里被称为路易体（LB）障碍（LBD），都共享LB和路易神经突（LN）。 神经元内病理学由聚集的α-突触核蛋白（aSyn）组成。LBD、PDD和阿尔茨海默病（AD） 具有（AD+aSyn）或不具有LB（AD-aSyn）的痴呆是最常见的衰老相关性痴呆。此外，LBD， AD+aSyn和多系统萎缩（MSA），以神经胶质细胞质内含物中错误折叠的aSyn为特征 （GCI）是主要的神经退行性突触核蛋白病。这种临床特征和aSyn 神经退行性疾病患者大脑中的神经病理学为这种菌株提供了间接支持 假设其中病理性aSyn采用不同的构象或菌株，这些构象或菌株导致临床和 这些疾病之间的病理异质性。此外，我们提出了传输假设， aSyn菌株以解释LBD、AD+aSyn和MSA进展的变异性。然而，这两种假设 需要严格的测试。最近，项目I和II的研究人员合作证明，纹状体内 将重组aSyn预形成的原纤维（PFF）注射到野生型（WT）小鼠中诱导了模板化的细胞凋亡。 内源性aSyn的错误折叠和聚集，其在纹状体连接体中逐渐扩散， 形成PD样LB和LN，随后黑质延髓部多巴胺能（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得到了许多其他国家的证实。 实验室，并扩展到大鼠和非人灵长类动物（见项目中的初步非人灵长类动物数据 （2）支持传播假说。这些验证性研究还表明，这些新的 模型概括了LBD的发病机制，将促进LBD的研究。我们还发现了不同的aSyn 通过人工合成的合成酶的体外连续繁殖， 从重组aSyn产生aSyn PFF，并且我们已经分离了不同的人LBD、AD+aSyn和MSA 来自LBD和AD+aSyn的aSyn菌株，以及在遗传和神经病理学上表征的MSA脑 核心C，来自患者，随后是核心B，并在项目III和IV中进行临床研究，从而进行合作 连接所有U19项目和核心。这些研究定义了来自AD+aSyn和LBD脑的不同aSyn菌株 命名为aSyn-LB（LB+LN）和来自MSA脑的命名为aSyn-GCI。这些和其他初步 数据为研究aSyn菌株在这种新的疾病中传播的致病机制提供了框架。 U19中心申请。为此，我们将使用生物化学、生物物理学和细胞生物学方法， 确定aSyn-LB和aSyn-GCI菌株的分子特征，并鉴定细胞的决定簇 型特异性，并阐明这些菌株的模板繁殖机制。