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

项目IV：病理性α-突触核蛋白菌株和多种突触核病 项目IV负责人：J.Q.Trojanowski；联合调查员：V.M.-Y.Lee和K.Luk 项目四摘要/摘要 在这里，我们测试了帕金森病中α-突触核蛋白(a-syn)病理进展的假设 (PD)无痴呆或伴痴呆(PDD)和路易体痴呆(DLB)代表不同a-DNA的扩散。 神经细胞中的SYN菌株被称为路易小体(LBS)和轴突(LNS)。我们将这些进行比较 多系统萎缩症(MSA)胶质细胞质内含物中的菌株相互之间以及与a-syn菌株的相互作用 (GCI)。这将有助于深入了解a-syn菌株是如何导致临床和病理异质性的。 这些不同的联体核病。由于PDD和DLB型痴呆常常伴有阿尔茨海默氏症 疾病(AD)，我们还将检验来自PD/PDD/DLB脑内的a-syn菌株(命名为Lb-a-a- SYN)诱导A-β和tau病理，与病理性a-SYN(命名为gci-a-syn)进行比较。 项目IV与项目III合作，后者在体外进行a-SYN株系研究，并为项目IV提供 从死后PD/PDD/DLb和MSA脑组织中分离到的A-syn菌株以及体外扩增的Lb和GCI a-syn 菌株。活着的受试者在核心B和项目I/II中进行研究，他们的大脑通过核心C获得 而Core 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/项目一起确定Lb-a-syn和GCI-a-syn菌株是否有差异诱导 病理性a-syn在神经元与胶质细胞以及招募AD样斑块和缠结病理，这将是 在野生型(WT)小鼠脑内注射后完成，人WT a-syn转基因(TG)小鼠(线61) 在小鼠a-syn基因敲除(KO)背景(KO61)和CNP-a-syn(M2)转基因小鼠中 (KOM2)Aβ(5xFAD，Tg2576，APP敲入)或tau(PS19)的GCIS模型与TG鼠标模型 病理学。在项目IV中检验的假设来自于在这个筹资周期中使用合成a- Syn预制纤维，我们现在通过使用lb-a-syn和gci-a-syn进行创新，在证明它们是 生物学上不同的a-syn菌株，GCI-a-syn的效力约为Lb-a-syn的1000倍。因此，我们测试 Pd/PDD/DLb与MSA的新假说来自不同的a-syn株。

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.