Propagation of Lewy pathology in Parkinsons disease

帕金森病中路易病理学的传播

• 批准号: 9242081
• 负责人: Kelvin C Luk
• 金额: $ 35万
• 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 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242081
• 关键词: Address; Affect; Amino Acid Sequence; Amyloid; Amyloid Fibrils; Amyloid beta-Protein; Animal Model; Animals; Area; Autopsy; Axon; Behavioral; Binding; Biological; Brain; Brain Diseases; Brain Stem; Brain region; Cell Death; Cell physiology; Cells; Characteristics; Collection; Cytoplasm; Deposition; Development; Disease; Disease Progression; Dopamine; Event; Exposure to; Family; Genetic; Histologic; Human; Hybrids; Impairment; In Vitro; Individual; Injectable; Injection of therapeutic agent; Interneurons; Investigation; Lead; Lesion; Lewy Bodies; Libraries; Link; Mediating; Methods; Modeling; Molecular; Mus; Mutagenesis; Mutation; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neurologic Symptoms; Neurons; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Pattern; Phenotype; Polymers; Prion Diseases; Prions; Process; Proteins; Proteomics; Recombinants; Research; Role; Route; SNCA gene; Seeds; Structure; Substantia nigra structure; Synapses; Testing; Transgenic Mice; alpha synuclein; base; behavior test; brain cell; catalyst; dopaminergic neuron; in vivo; insight; locomotor deficit; misfolded protein; motor impairment; mouse synuclein alpha; mutant; neuron loss; novel; novel therapeutics; overexpression; pars compacta; public health relevance; synucleinopathy; tau Proteins; tissue processing; tool; transmission process; virtual

 DESCRIPTION (provided by applicant): The accumulation of misfolded proteins represents a common pathological mechanism of most major neurodegenerative disorders. Neuronal inclusions comprised of aggregated a-Synuclein (aSyn) are known as Lewy bodies (LBs) and Lewy-neurites (LNs), and represent a key histopathological feature of Parkinson's disease (PD), and a family of related disorders known as synucleinopathies that affect as many as 1 million individuals in the U.S. alone. Mutations in the SNCA gene encoding aSyn also cause familial PD but while histological and genetic evidence firmly indicate a correlation between aSyn accumulation and disease, how aSyn pathology forms and whether it directly contributes to disease remains unclear. Abnormal aSyn catalyzes the misfolding of the normal protein and it has recently been demonstrated that minute quantities of aSyn aggregates can trigger the formation of toxic LBs/LNs in cultured neurons. Misfolded aSyn also induces the formation of LBs/LNs in healthy non-transgenic mice. In both human PD and animal models, 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 proposed research plan addresses key biological questions posed by these findings, and combines novel in vitro, cell-based, and in vivo tools to further understand how LBs/LNs are form, propagate, and ultimately contribute to neurodegeneration and neurological symptoms. Aim 1 examines whether neurons in multiple brain regions develop LBs/LNs following inoculation with misfolded recombinant aSyn and subsequently undergo cell death. A recently developed tissue processing method will be used to determine if LBs/LNs spread via neuronal projections, as hypothesized for human PD, or by other mechanisms. Behavioral tests will then reveal if specific clinicopathological correlations exist. Aim 2 will define the molecular interactions that govern how abnormal aSyn triggers the conversion of normal aSyn in LBs/LNs, by testing the ability of mutant aSyn sequences to seed pathology in both cells and in vivo following stereotactic injection. Finally, Aim 3 will elucidate the cellular and molecular mechanisms by which aSyn induce intracellular pathology by using cell-based, in vivo, and proteomics approaches to compare LB/LN-inducing and non-inducing aSyn mutants that we have recently discovered. Completion of these studies should provide valuable insights into the potential mechanisms by which aSyn contribute to the progression of PD. Increased understanding of the pathogenesis of this and related synucleinopathies should ultimately result in disease-modifying therapies for this group of incurable disorders.

 描述（由申请方提供）：错误折叠蛋白的积累代表了大多数主要神经退行性疾病的常见病理机制。由聚集的α-突触核蛋白（aSyn）组成的神经元内含物被称为路易体（LB）和路易神经突（LN），并且代表帕金森病（PD）的关键组织病理学特征，以及仅在美国就影响多达100万个体的被称为突触核蛋白病的相关病症家族。编码aSyn的SNCA基因的突变也会导致家族性PD，但尽管组织学和遗传学证据明确表明aSyn积累与疾病之间存在相关性，但aSyn病理学如何形成以及它是否直接导致疾病仍不清楚。异常aSyn催化正常蛋白质的错误折叠，并且最近已经证明，微量的aSyn聚集体可以触发培养的神经元中毒性LB/LN的形成。错误折叠的aSyn还诱导健康非转基因小鼠中LB/LN的形成。在人类PD和动物模型中，aSyn病理学逐渐传播并扩散到神经解剖学连接的区域，使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进行性丧失和运动缺陷。这项拟议的研究计划解决了这些发现提出的关键生物学问题，并结合了新的体外、基于细胞的和体内工具，以进一步了解LB/LN是如何形成、传播并最终导致神经变性和神经症状的。目的1检查多个脑区域中的神经元是否在接种错误折叠的重组aSyn后发展LB/LN并随后经历细胞死亡。最近开发的组织处理方法将用于确定LB/LN是否通过神经元投射传播，如对人类PD的假设，或通过其他机制。然后，行为测试将揭示是否存在特定的临床病理学相关性。目的2将通过测试突变体aSyn序列在立体定向注射后在细胞和体内接种病理的能力，定义控制异常aSyn如何触发LB/LN中正常aSyn转化的分子相互作用。最后，目标3将阐明细胞和分子机制，通过使用基于细胞的，在体内，和蛋白质组学的方法来比较LB/LN诱导和非诱导aSyn突变体，我们最近发现的aSyn诱导细胞内病理。这些研究的完成应该为aSyn促进PD进展的潜在机制提供有价值的见解。对这种和相关的突触核蛋白病的发病机制的了解的增加最终将导致这组无法治愈的疾病的疾病修饰疗法。