Membrane Curvature Sensing Mechanisms for Synaptic Vesicle Endocytosis

项目摘要 内吞作用在支持人类大脑的健康方面起着至关重要的作用。功能上，突触囊泡 内吞作用允许神经元维持突触传递而不耗尽突触传递的供应。 囊泡在结构上，内吞作用支持突触和神经回路的维持。因此，在本发明中， 有缺陷的突触囊泡内吞作用造成神经传递的缺陷，这些缺陷是广泛的 神经系统疾病和精神障碍。这项研究的长期目标是确定内吞作用是如何发生的。 蛋白质协同作用以支持突触内吞作用的不同途径。来自多个实验室的工作 包括我在内的研究人员发现，曲率感应蛋白质内啡肽在突触中起着关键作用。 囊泡内吞作用在这个提议中，我们将检验曲率感知机制引导 内吞蛋白在各种内吞途径中发挥其功能。我们提出三个具体目标。 1)我们将在体内确定曲率敏感基序的作用。我们专注于曲率感应 内亲蛋白的两亲性螺旋，因为它是突触囊泡内吞作用所必需的。2)我们将研究如何 曲率信号由下游蛋白synaptojanin接收以支持突触囊泡 内吞作用，并防止突触传递的年龄依赖性衰减。3)康贝特人将以 内嗜蛋白非依赖性内吞作用的机制，这是一个缺乏分子信息的领域。通过 无偏见的遗传筛选，我们已经确定了另一个曲率感应蛋白，在一个平行的途径 用内啡肽这些研究的结果预计将推动目前知识的界限， 突触生物学，并导致解决神经系统疾病。

Project Summary Endocytosis plays a crucial role in supporting the health of the human brain. Functionally, synaptic vesicle endocytosis allows neurons to sustain synaptic transmission without exhausting the supply of synaptic vesicles. Structurally, endocytosis supports the maintenance of synapses and neural circuits. As a result, defective synaptic vesicle endocytosis creates deficits in neurotransmission that underlie a wide spectrum of neurological diseases and psychiatric disorders. The long-term goal of this study is to determine how endocytic proteins act in concert to support diverse routes of endocytosis at synapses. Work from several laboratories including my own has found that the curvature-sensing protein endophilin plays a critical role in synaptic vesicle endocytosis. In this proposal, we will examine the hypothesis that curvature-sensing mechanisms guide endocytic proteins to perform their function in various routes of endocytosis. We propose three Specific Aims. 1) We will determine the role of curvature-sensing motifs in vivo. We focus on the curvature-sensing amphipathic helix of endophilin as it is essential for synaptic vesicle endocytosis. 2) We will study how curvature signals are received by the downstream protein synaptojanin to support synaptic vesicle endocytosis, and to prevent age-dependent decay of synaptic transmission. 3) We will determine the mechanism of endophilin-independent endocytosis, an area that lacks molecular information. Through an unbiased genetic screen, we have identified another curvature-sensing protein that acts in a parallel pathway with endophilin. Results from these studies are expected to to push boundaries of current knowledge of synaptic biology and to lead toward solutions for neurological disorders.