The Physiological Functions of Synucleins

突触核蛋白的生理功能

• 批准号: 8284375
• 负责人: Sreeganga S Chandra
• 金额: $ 31.93万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8284375
• 关键词: Adopted; Affect; Binding; Binding Proteins; Biochemical; Biological Assay; Biology; Brain; Cell Death; Circular Dichroism; Data; Demographic Aging; Development; Disease; Disease Progression; Early treatment; Electrons; Endocytosis; Etiology; Event; Family; Functional disorder; Gene Dosage; Generations; Genes; Genetic Polymorphism; Goals; Gray unit of radiation dose; Health; Hippocampus (Brain); Human; Image; Knockout Mice; Knowledge; Lewy Bodies; Link; Membrane; Membrane Proteins; Microscopic; Modeling; Molecular; Molecular Conformation; Morphology; Mus; Mutation; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenesis; Patients; Phenotype; Physiological; Physiology; Play; Point Mutation; Presynaptic Terminals; Prevalence; Promoter Regions; Property; Proteins; Proteomics; Regulation; Research; Risk; Role; Societies; Staging; Symptoms; Synapses; Synaptic Transmission; Synaptic Vesicles; Testing; Therapeutic Intervention; Time; Transgenic Mice; Transgenic Organisms; Work; alpha synuclein; base; demographics; design; gain of function; in vivo; insight; loss of function; member; mouse model; mutant; neurotransmission; novel; optical imaging; overexpression; presynaptic; prevent; public health relevance; research study; synuclein; therapeutic target

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a progressive neurodegenerative disease affecting millions of people. Synaptic dysfunction is an early event in the pathogenesis of the disease occurring prior to the onset of symptoms. Therapeutic interventions at these early stages hold the promise of slowing or even halting the disease. The biggest obstacle to the development of such therapies is a lack of knowledge of early molecular and synaptic events that occur in PD. Therefore, our long term objective is to understand the mechanisms of synaptic dysfunction in PD. a-Synuclein was the first gene identified to cause dominant familial PD, and is also the major constituent of Lewy bodies, the pathological hallmarks of PD. Hence, considerable effort is being directed at understanding the role of a-synuclein in the pathogenesis of PD. However, these efforts are focused mostly on toxic gain-of- function approaches, such as its aggregation. In contrast, little is known about the normal physiological functions of a-synuclein at the presynaptic terminal and its contribution to PD. This is the objective of our proposal. We have generated a novel mouse that lacks all synucleins to facilitate these studies. To attain the objective of this application, three aims are pursued. First, the interaction of synucleins with newly identified physiological partners and the bilayer will be examined. Second, the synaptic transmission deficits of synuclein null neurons will be characterized in culture and in vivo. Third, we will study how PD mutations impact these physiological properties and functions. Achieving these goals is important for human health, given aging demographics and the increasing prevalence of neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: a -Synuclein is a protein that forms clumps in the brains of Parkinson's patients. We are investigating what the normal function of a-synuclein is in the brain and whether alterations of this function plays a part in Parkinson's disease. This study will allow us, in time, to design early therapies for preventing cell death in Parkinson's disease.

描述（由申请人提供）：帕金森病（PD）是一种影响数百万人的进行性神经退行性疾病。突触功能障碍是在症状发作之前发生的疾病发病机制中的早期事件。在这些早期阶段的治疗干预有望减缓甚至阻止疾病。发展这种疗法的最大障碍是缺乏对PD中发生的早期分子和突触事件的了解。因此，我们的长期目标是了解PD中突触功能障碍的机制。α-突触核蛋白是第一个被鉴定为引起显性家族性PD的基因，并且也是路易体的主要成分，路易体是PD的病理标志。因此，相当大的努力是针对理解的作用，α-突触核蛋白在PD的发病机制。然而，这些努力主要集中在毒性功能获得方法上，例如其聚集。与此相反，很少有人知道的正常生理功能的α-突触核蛋白在突触前终端和它的贡献PD。这是我们建议的目的。我们已经产生了一种新的小鼠，缺乏所有的突触核蛋白，以促进这些研究。为了实现本申请的目的，追求三个目标。首先，将检查突触核蛋白与新鉴定的生理伴侣和双分子层的相互作用。第二，突触核蛋白空神经元的突触传递缺陷将在培养和体内表征。第三，我们将研究PD突变如何影响这些生理特性和功能。鉴于人口老龄化和神经退行性疾病的日益普遍，实现这些目标对人类健康至关重要。 公共卫生相关性：α-突触核蛋白是一种在帕金森病患者大脑中形成团块的蛋白质。我们正在研究α-突触核蛋白在大脑中的正常功能，以及这种功能的改变是否在帕金森病中起作用。这项研究将使我们能够及时设计预防帕金森病细胞死亡的早期疗法。