Propagation of Lewy pathology in Parkinson's and related disorders

路易病理学在帕金森病及相关疾病中的传播

• 批准号: 10347322
• 负责人: Kelvin C Luk
• 金额: $ 47.4万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-13 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10347322
• 关键词: Address; Affect; Alzheimer' s Disease; Alzheimer' s disease patient; Animal Model; Animals; Antisense Oligonucleotides; Atlases; Autopsy; Biological; Brain; Brain Diseases; Brain Stem; Candidate Disease Gene; Cell Separation; Cells; Cytoplasm; Data; Dementia with Lewy Bodies; Deposition; Development; Disease; Disease Progression; Disease model; Distal; Dopamine; Early Diagnosis; Exposure to; Family; Funding; Gene Expression; Genes; Genetic; Histologic; Human; Impairment; Individual; Infectious Agent; Injections; Knock-in; Knock-in Mouse; Knock-out; Label; Lead; Lesion; Lewy Bodies; Lewy body pathology; Lewy neurites; Libraries; Link; Literature; Maps; Measures; Mediating; Methods; Modeling; Molecular; Molecular Genetics; Molecular Profiling; Mus; Mutation; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurologic Symptoms; Neurons; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Pattern; Peripheral Nervous System; Population; Prion Diseases; Process; Proteins; Rattus; Recombinants; Reporting; Resistance; SNCA gene; Seeds; Site; Structure; Substantia nigra structure; Testing; Time; Tissues; Toxic effect; Tracer; Wild Type Mouse; alpha synuclein; base; brain cell; candidate marker; computerized tools; connectome; differential expression; dopaminergic neuron; gene expression database; genetic risk factor; human disease; in silico; in vivo; insight; knock-down; locomotor deficit; mathematical methods; mathematical model; misfolded protein; motor impairment; neuron loss; neuronal survival; nonhuman primate; novel; novel therapeutics; pars compacta; pre-formed fibril; risk variant; single-cell RNA sequencing; spatiotemporal; synucleinopathy; tool; transcriptome sequencing; virtual

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.

错误折叠的蛋白质堆积是大多数主要的 神经退行性疾病。由聚集的α-突触核蛋白(ASyn)组成的神经元包涵体，称为 路易小体(LBS)和路易神经纤维(LNS)是帕金森氏病的重要组织病理学特征 帕金森病(PD)和一系列称为联核病的相关疾病，最著名的是伴有LBS的痴呆症(DLB)。 在近一半的阿尔茨海默病患者中，LBS也是一个突出的特征。基因的突变和扩增 编码aSyn的SNCA基因也会导致家族性帕金森病。尽管大量的组织学和 遗传证据确凿地表明，a Syn的积累与疾病之间存在相关性，目前尚不清楚是如何 ASyn病理实际上形成并随后促成了疾病。我们和其他人最近展示了 微量的重组或患者衍生的aSyn聚集体可以催化有毒物质的形成 LBS/LNS在培养的神经元和健康的非转基因小鼠中。在人类帕金森病和动物模型中，这 “播种的”aSyn病理逐渐传播和扩散到神经解剖学上连接的区域， 让人想起普恩病毒的疾病。重要的是，患有LBS/LNS的动物概括了PD的基本特征， 包括产生多巴胺的神经元的进行性丧失和运动障碍。 R01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LBS/LNS如何形成、传播和最终 会导致神经退化和神经症状。目标1将在神经元亚型上识别 用错误折叠的aSyn接种后形成LBS/LNS。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 易受或抵抗LBS/LNS形成的亚群。Aim 2将研究帕金森病的遗传风险 文献中报道的因素与Syn病理生物学交叉，通过测试击倒或敲打的效果- 研究单个基因对种子病理形成和神经元存活的影响。候选人显著地 任何一种改变都将在体内使用敲除/敲入小鼠品系进行确认。最后，目标3将整合我们的 分子、遗传和活体实验数据，以及公开可用的连接性和基因- 表达图谱，以询问病理传播的机制。使用最近开发的 描述感染剂传播的数学方法，我们将在计算机模型中发展来理解 ASyn病理形成和扩散。这些研究的完成应该会为我们提供对 ASyn促进帕金森病及相关疾病进展的潜在机制。增加了 对这种疾病和相关的联体核病的发病机制的理解最终应该导致更早的 对这些目前无法治愈的疾病进行检测和疾病修正治疗。