The Physiological Functions of Synucleins

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。突触功能障碍是发病机制的早期事件，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。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。a-Synuclein是第一个被发现导致显性家族性PD的基因，也是PD的病理标志路易小体的主要成分。因此，大量的工作被用于了解a-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毒性功能获得方法上，例如其聚集。相比之下，a-synuclein在突触前末端的正常生理功能及其对PD的作用知之甚少。这就是我们提议的目标。我们已经产生了一种缺乏所有突触核蛋白的新型小鼠来促进这些研究。为了实现这一应用的目标，需要达到三个目标。首先，将研究突触核蛋白与新发现的生理伙伴和双分子层的相互作用。其次，将在培养和体内研究突触核蛋白缺失神经元的突触传递缺陷。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流行，实现这些目标对人类健康至关重要。

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.