Propagation of Lewy pathology in Parkinson's and related disorders

错误折叠蛋白质的积累代表了大多数主要疾病的共同病理机制。 神经退行性疾病神经元包涵体由聚集的α-突触核蛋白（aSyn）组成，称为 路易体和路易神经突是帕金森病的重要病理组织学特征 (PD)以及称为突触核蛋白病的相关疾病家族，最著名的是LB痴呆（DLB）。 LB也是近一半阿尔茨海默病受试者的突出特征。突变和扩增 编码aSyn SNCA基因也引起家族性PD。虽然大量的组织学和 遗传证据坚定地表明aSyn积累与疾病之间的相关性，但仍不清楚如何 aSyn病理实际上形成并随后促成疾病。我们和其他人最近展示了 微量的重组体或患者来源的aSyn聚集体可以催化有毒的细胞因子的形成。 LB/LN在培养的神经元和健康的非转基因小鼠。在人类PD和动物模型中， “播种的”aSyn病理学逐渐传播并扩散到神经解剖学连接的区域， 让人联想到朊病毒疾病重要的是，具有LB/LN的动物概括了PD的主要特征， 包括产生多巴胺的神经元的逐渐丧失和运动缺陷。 这种R 01更新解决了我们早期发现提出的几个关键生物学问题，并结合了新的 分子，体内和计算工具，以进一步了解LB/LN如何形成，传播，并最终 导致神经退化和神经症状。Aim 1将识别神经元亚型， 在用错误折叠的aSyn接种后发展LB/LN。通过将传统的组织学方法与 FACS辅助的单神经元RNAseq，我们将确定与 对LB/LN形成脆弱或具有抗性的亚群。目标2将研究PD遗传风险如何 文献中报道的因素与aSyn病理生物学交叉，通过测试敲低或敲低的影响， 在个别基因的形成种子病理和神经元存活。候选人， 将使用敲除/敲入小鼠系在体内证实改变。最后，目标3将整合我们的 分子、遗传和体内实验数据以及公开可用的连接性和基因- 表达图谱来询问病理扩散的机制。利用最近开发的 数学方法来描述传染性病原体的传播，我们将开发计算机模型，以了解 aSyn病理形成和传播。这些研究的完成应能提供宝贵的见解， aSyn促进PD和相关病症进展的潜在机制。增加 了解这种和相关的突触核蛋白病的发病机制， 这些目前无法治愈的疾病的检测和疾病修饰疗法。

The accumulation of misfolded proteins represents a common pathological mechanism of most major neurodegenerative disorders. Neuronal inclusions comprised of aggregated α-Synuclein (aSyn), known as Lewy bodies (LBs) and Lewy-neurites (LNs), represent a key histopathological feature of Parkinson's disease (PD) and a family of related disorders known as synucleinopathies, most notably Dementia with LBs (DLB). LBs are also a prominent feature in nearly half of Alzheimer's disease subjects. Mutations and amplifications in the SNCA gene encoding aSyn also cause familial forms of PD. Although a large body of histological and genetic evidence firmly indicate a correlation between aSyn accumulation and disease, it remains unclear how aSyn pathology actually forms and subsequently contributes to disease. We and others recently demonstrated that minute quantities of recombinant or patient-derived aSyn aggregates can catalyze the formation of toxic LBs/LNs in cultured neurons and healthy non-transgenic mice. In both human PD and animal models, this “seeded” aSyn pathology progressively propagates and spreads to neuroanatomically connected regions, reminiscent of prion diseases. Importantly, animals with LBs/LNs recapitulate the cardinal features of PD, including progressive loss of dopamine-producing neurons and locomotor deficits. This R01 renewal addresses several key biological questions posed by our earlier findings and combines novel molecular, in vivo, and computational tools to further understand how LBs/LNs form, propagate, and ultimately contribute to neurodegeneration and neurological symptoms. Aim 1 will identify at the neuron subtypes that develop LBs/LNs following inoculation with misfolded aSyn. By combining traditional histological methods with FACS-assisted single-neuron RNAseq, we will determine the molecular signatures associated with subpopulations that are vulnerable or resistant to LBs/LNs formation. Aim 2 will examine how PD genetic risk factors reported in the literature intersect with aSyn pathobiology, by testing the effect of knock-down or knock- in of individual genes on the formation of seeded pathology and neuronal survival. Candidates that significantly alter either will be confirmed in vivo using knock-out/knock-in mouse lines. Lastly, Aim 3 will integrate our molecular, genetic, and in vivo experimental data together with publicly available connectivity and gene- expression atlases to interrogate the mechanisms of pathological spread. Using recently developed mathematical approaches to describe infectious agent spread, we will develop in silico models to understand aSyn pathology formation and spread. Completion of these studies should provide valuable insights into the potential mechanisms by which aSyn contribute to the progression of PD and related disorders. Increased understanding of the pathogenesis of this and related synucleinopathies should ultimately result in earlier detection and disease-modifying therapies for these currently incurable disorders.