Pathological spread and outcomes of alpha-synuclein mutants

α-突触核蛋白突变体的病理传播和结果

• 批准号: 9374238
• 负责人: BENOIT I GIASSON
• 金额: $ 19.06万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9374238
• 关键词: Address; Amyloid Fibrils; Automobile Driving; Brain; Cell Death; Cell physiology; Cells; Characteristics; Complex; Cultured Cells; Data; Disease; Disease Progression; Etiology; Experimental Models; Genes; Genetic study; Impairment; In Vitro; Lewy Body Dementia; Light; Link; Missense Mutation; Molecular Conformation; Mutation; Nature; Nerve Degeneration; Nervous System Heredodegenerative Disorders; Nervous system structure; Neurodegenerative Disorders; Neuroglia; Neuronal Dysfunction; Neurons; Outcome; Parkinson Disease; Parkinson' s Dementia; Pathologic; Pathology; Patients; Peripheral Nervous System; Physiological; Property; Proteins; Publishing; Research Personnel; Role; Severity of illness; Staining method; Stains; Substantia nigra structure; Testing; Toxic effect; alpha synuclein; dopaminergic neuron; early onset; experience; in vivo; insight; mutant; neurotoxicity; novel; prion-like; protein aggregation; protein complex; synuclein; synucleinopathy; transmission process

Project Summary/Abstract The progressive accumulation of -synuclein intracellular inclusions in the nervous system is a characteristic feature of dementia with Lewy bodies and Parkinson's disease which are part of a spectrum of sporadic and hereditary neurodegenerative diseases termed -synucleinopathies. The definitive involvement of -synuclein in the etiology of these disorders was established by the findings that mutations in -synuclein can directly cause these neurodegenerative disorders. Many studies suggest that the progressive spread of -synuclein pathology in the peripheral nervous system and the brain through direct -synuclein interactions and transmission between cells may contribute to disease progression. However, some studies characterizing the properties of novel - synuclein mutants demonstrated divergent effects that are not consistent with this simple spreading mechanism. It is also important to emphasize that there is still ongoing debate as to the nature of the toxic α-synuclein species. To provide new insights on these contentious and critical issues that will address the unique properties of disease-associated -synuclein mutants, we have formed a team of experienced investigators with diverse and unique expertise. In Aim 1, we will determine the inherent aggregation and neurotoxicity properties of these novel -synuclein mutants in vivo and compare these outcomes to the more extensively characterized -synuclein mutants. In Aim 2, we will test the hypothesis that in vivo prion-like seeding can differentially impact the induction and propagation of -synuclein inclusion pathology of disease-causal -synuclein mutants with unique stain-like properties. These studies will provide pivotal information regarding the neurotoxicity of abnormal forms of - synuclein, their impact of the induction and spread of -synuclein pathology and the associations with neurodegeneration.

项目总结/摘要 神经系统中β-突触核蛋白胞内包涵体的进行性积累是一个特征 路易体痴呆症和帕金森病的特征，这些疾病是散发性和 遗传性神经退行性疾病称为突触核蛋白病。β-突触核蛋白的明确参与 在这些疾病的病因学是建立在发现β-突触核蛋白的突变可以直接导致 这些神经退行性疾病许多研究表明β-突触核蛋白病理学的进行性传播 在周围神经系统和大脑中通过直接的β-突触核蛋白相互作用和之间的传输 细胞可能有助于疾病的进展。然而，一些研究表征了新的生物活性物质的性质， 突触核蛋白突变体表现出与这种简单的扩散机制不一致的发散效应。 同样重要的是要强调，关于有毒α-突触核蛋白种类的性质仍有持续的争论。 就这些有争议的关键问题提供新的见解，这些问题将解决 疾病相关的β-突触核蛋白突变体，我们已经形成了一个经验丰富的研究团队， 独特的专业知识。在目标1中，我们将确定这些新的聚乙二醇的固有聚集和神经毒性性质。 在体内的β-突触核蛋白突变体，并比较这些结果更广泛的特点β-突触核蛋白 变种人在目标2中，我们将测试体内朊病毒样接种可以不同地影响诱导的假设， 致病性β-突触核蛋白突变体的病理学 特性.这些研究将提供关于异常形式的神经毒性的关键信息， 突触核蛋白，它们对β-突触核蛋白病理学的诱导和传播的影响，以及与 神经变性