The Physiological Functions of Synucleins

描述(申请人提供)：帕金森病(PD)是一种进行性神经退行性疾病，影响数百万人。突触功能障碍是该病发病机制中的一个早期事件，发生在症状出现之前。在这些早期阶段进行治疗干预有望减缓甚至阻止这种疾病。这类疗法发展的最大障碍是缺乏对帕金森病早期分子和突触事件的了解。因此，我们的长期目标是了解帕金森病患者突触功能障碍的机制。A-突触核蛋白是第一个被发现的导致显性家族性帕金森病的基因，也是帕金森病的病理标志--路易小体的主要成分。因此，人们正致力于了解α-突触核蛋白在帕金森病发病机制中的作用。然而，这些努力主要集中在有毒的功能收益方法上，例如它的聚合。相比之下，人们对突触前终末α-突触核蛋白的正常生理功能及其对帕金森病的贡献知之甚少。这就是我们建议的目标。我们已经创造了一种新型的小鼠，它缺乏所有的突触核蛋白，以促进这些研究。为了达到这一应用的目标，我们追求了三个目标。首先，我们将研究突触核蛋白与新发现的生理伙伴和双层之间的相互作用。第二，突触核蛋白缺失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日益普遍，实现这些目标对人类健康非常重要。 与公共健康相关：A-突触核蛋白是一种蛋白质，可以在帕金森氏症患者的大脑中形成团块。我们正在研究a-突触核蛋白在大脑中的正常功能，以及这一功能的改变是否在帕金森病中起到了作用。这项研究将使我们能够及时设计出预防帕金森氏症细胞死亡的早期治疗方法。

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.