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α-突触核蛋白的传播和菌株” 项目负责人：弗吉尼亚州M.-Y.李 项目I摘要/摘要 项目I，以前是III项目，随着项目I的重新编号，以改善我们重新提交的项目的流程 新的U19赠款名为“阿尔茨海默氏病和相关痴呆症中α-突触核蛋白菌株中心” 宾夕法尼亚大学（Penn）Perelman医学院（PSOM）测试传播和应变 A-突触核疾病的假设。 Lewy Bodies（DLB），帕金森氏病（PD）的痴呆症没有和 与痴呆症（PDD）一起称为Lewy身体（LB）疾病（LBD），全部共享LB和Lewy Neurote（LN） 骨内病理综合α-核蛋白（ASYN）完成。 LBD，PDD和阿尔茨海默氏病（AD） 使用（AD+ASYN）或不含LBS（AD-ASYN）是最常见的与衰老相关的痴呆症。而且，LBD， AD+ASYN和多系统萎缩（MSA），其特征是胶质细胞胞质夹杂物中的Asyn折叠率折叠率不当 （GCIS）是主要神经退行性突触性核酸疾病。临床特征和ASYN的多样性 神经退行性疾病患者大脑中的神经病理学为菌株提供间接支持 假设病理性ASYN采用不同的考虑因素或菌株，这些因素是临床和 这些疾病之间的病理异质性。此外，我们提出了传播假设 Asyn菌株解释了LBD，AD+ASYN和MSA进展的变化。但是，这两个假设 需要严格的测试。最近，项目I和II调查人员合作证明了纹状体 注射重组ASYN预制的原纤维（PFF）中的野生型（WT）小鼠诱导了模板 内源性ASYN的错误折叠和聚集，这些Asyn逐渐跨纹状体连接组逐渐扩散到 形式类似Pd的LB和LNS，然后在底底nigra pars compacta中多巴胺能（DA）神经元丧失 PD（SNPC）和运动障碍的特征。我们的主要观察结果已得到许多其他的验证 实验室并扩展到大鼠和非人类灵长类动物（请参阅项目的初步非人类灵长类动物数据 ii）从而支持传播假设。这些确认研究还表明这些新颖 模型概括了LBD发病机理，并将促进LBD研究。我们还确定了独特的Asyn 通过合成的序列体外传播具有不同会议和生物活性的菌株 由重组ASYN产生的Asyn PFF，我们分离了不同的人LBD，AD+ASYN和MSA 来自LBD和AD+ASYN的Asyn菌株以及MSA大脑在遗传学和神经病理上的特征 由患者的核心C，然后在III和IV项目中进行核心B和Studiod在临床上进行研究 将所有U19项目和核心联系起来。这些研究定义了AD+ASYN和LBD大脑的不同ASYN菌株 被指定为Asyn-LB（LB+LN），并从称为Asyn-GCI的MSA大脑。这些和其他初步 数据提供了研究此新的ASYN应变传播的致病机制的框架 U19中心申请。为此，我们将使用生化，生物物理和细胞生物学方法来 确定ASYN-LB和ASYN-GCI菌株的分子特征，并识别细胞的决定剂 每个应变的类型规格，并阐明这些菌株模板传播的机制。