Project IV: "Alpha-Synuclein Strains & Diverse Synucleinopathies"

项目四：“α-突触核蛋白菌株

• 批准号: 9402331
• 负责人: JOHN Q. TROJANOWSKI
• 金额: $ 35.41万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9402331
• 关键词: Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Autopsy; Bioinformatics; Biological; Biology; Biometry; Brain; Clinical; Comorbidity; Complement; Cytoplasmic Inclusion; Data; Dementia; Funding; Heterogeneity; Hippocampus (Brain); Human; In Vitro; Injectable; Injection of therapeutic agent; Knock-in; Knock-out; Lewy Bodies; Lewy Body Dementia; Methods; Modeling; Molecular Conformation; Multiple System Atrophy; Mus; Nerve Degeneration; Neurites; Neurofibrillary Tangles; Neuroglia; Neurons; Oligodendroglia; Parkinson Disease; Parkinson' s Dementia; Pathologic; Pathology; Patients; Property; Protein Precursors; Recruitment Activity; Research Personnel; Seeds; Study Subject; Testing; Tg2576; Transgenic Mice; Wild Type Mouse; Work; alpha synuclein; cerebral atrophy; data management; in vitro Model; in vivo; in vivo Model; innovation; insight; mouse model; mutant; novel; synucleinopathy; tau Proteins

PROJECT IV: Pathologic Alpha-synuclein Strains & Diverse Synucleinopathies Project IV Leader: J.Q. Trojanowski; Co-Investigators: V.M.-Y. Lee & K. Luk Project IV Summary/Abstract Here we test the hypothesis that progression of alpha-synuclein (a-syn) pathology in Parkinson's disease (PD) without or with dementia (PDD) and dementia with Lewy bodies (DLB) represent the spread of different a- syn strains in neurons where they are known as Lewy bodies (LBs) and neurites (LNs). We compare these strains to each other and with a-syn strains in multiple system atrophy (MSA) glial cytoplasmic inclusions (GCI). This will advance insights into how distinct a-syn strains drive clinical and pathological heterogeneity in these diverse synucleinopathies. Since dementia in PDD and DLB frequently is accompanied by Alzheimer's disease (AD), we also will test the hypothesis that a-syn strains from PD/PDD/DLB brains (designated LB-a- syn) induce Aβ and tau pathologies compared to pathological a-syn from MSA brains (designated GCI-a-syn). Project IV collaborates with Project III, which performs in vitro a-syn strain studies and provides Project IV with a-syn strains from postmortem PD/PDD/ DLB and MSA brains as well as in vitro amplified LB and GCI a-syn strains. Living subjects are studied in Core B and Projects I/II and their brains are obtained through Core C while Core D provides data management/biostatistics/bioinformatics support. Thus, Project IV works closely with all Udall Center Cores/Projects to determine if LB-a-syn and GCI-a-syn strains differentially induce pathological a-syn in neurons versus glia as well as recruit AD-like plaque and tangle pathology, This will be done following intracerebral injections into wild type (WT) mice, human WT a-syn transgenic (Tg) mice (line 61) in a mouse a-syn knock out (KO) background (KO61) and CNP-a-syn (M2) Tg mice in a-syn KO background (KOM2) that model GCIs versus Tg mouse models of Aβ (5xFAD, Tg2576, APP knock in) or tau (PS19) pathologies. The hypothesis tested in Project IV emerged from studies in this funding cycle using synthetic a- syn preformed fibrils, and we innovate now by using LB-a-syn and GCI-a-syn after showing that they are biologically distinct a-syn strains with GCI-a-Syn being ~1000 fold more potent than LB-a-syn. Hence, we test the novel hypothesis that PD/PDD/DLB versus MSA result from different a-syn strains.

项目IV：病理性α-突触核蛋白菌株和多种突触核蛋白病 项目四负责人：J.Q. Trojanowski;合作研究者：V.M. - y. Lee & K.陆 项目IV摘要/摘要 在这里，我们测试的假设，α-突触核蛋白（α-syn）的病理进展在帕金森氏病 (PD)无痴呆或有痴呆（PDD）和路易体痴呆（DLB）代表了不同的α- 在神经元中，它们被称为路易体（LB）和神经突（LN）。我们比较这些 多系统萎缩（MSA）胶质细胞胞质内含物中的α-syn菌株 （GCI）。这将推进对不同a-syn菌株如何驱动临床和病理异质性的深入了解， 这些不同的共核蛋白病由于PDD和DLB中的痴呆经常伴有阿尔茨海默氏症， 疾病（AD）中，我们还将测试来自PD/PDD/DLB脑的a-syn菌株（命名为LB-a- 与来自MSA脑的病理性a-syn（命名为GCI-a-syn）相比，来自MSA脑的病理性a-syn（命名为GCI-a-syn）诱导A β和tau病理。 项目IV与项目III合作，项目III进行体外a-syn菌株研究，并为项目IV提供 来自死后PD/PDD/DLB和MSA脑的a-syn菌株以及体外扩增的LB和GCI a-syn菌株 菌株核心B和项目I/II中研究活体受试者，通过核心C获得他们的大脑 而核心D提供数据管理/生物统计/生物信息学支持。因此，项目四密切合作， 与所有Udall中心核心/项目进行比较，以确定LB-a-syn和GCI-a-syn菌株是否差异诱导 病理性a-syn在神经元与神经胶质细胞以及招募AD样斑块和缠结病理，这将是 脑内注射野生型（WT）小鼠、人WT a-syn转基因（Tg）小鼠（第61系）后完成 在小鼠a-syn敲除（KO）背景（KO61）和a-syn KO背景中CNP-a-syn（M2）Tg小鼠中 （KOM2）模拟GCI与A β（5xFAD、Tg2576、APP敲入）或tau（PS19）的Tg小鼠模型 病理学项目四中检验的假设来自本供资周期中使用合成a- syn预成型的原纤维，我们现在通过使用LB-a-syn和GCI-a-syn进行创新，因为它们是 生物学上不同的a-syn菌株，其中GCI-a-Syn比LB-a-syn更有效约1000倍。因此，我们测试 PD/PDD/DLB相对于MSA的新假设来自不同的a-syn菌株。