Membrane Curvature Sensing Mechanisms for Synaptic Vesicle Endocytosis

项目摘要 内吞作用在维持人脑健康方面起着至关重要的作用。从功能上讲，突触小泡 内吞作用使神经元在不耗尽突触供应的情况下维持突触传递 水泡。在结构上，内吞作用支持突触和神经回路的维持。结果, 有缺陷的突触小泡内吞作用导致神经传递功能障碍，这是一系列 神经疾病和精神障碍。这项研究的长期目标是确定内吞如何 蛋白质协同作用支持突触内吞作用的不同途径。来自几个实验室的研究 包括我自己在内的研究人员发现，曲率感应蛋白内嗜素在突触中起着关键作用 囊泡内吞作用。在这个提案中，我们将检验曲率感应机制引导的假设 内吞蛋白在不同的内吞作用途径中发挥其功能。我们提出了三个具体目标。 1)我们将确定曲率感知基序在体内的作用。我们主要研究曲率传感技术。 亲内素的两亲性螺旋，因为它是突触囊泡内吞所必需的。2)我们将研究如何 曲率信号由下游的突触素蛋白接收，以支持突触小泡 内吞作用，并防止突触传递的年龄依赖性衰退。3)我们将确定 缺乏分子信息的亲内素非依赖性内吞作用的机制。通过一个 在无偏见的遗传筛选中，我们发现了另一种以平行途径起作用的曲率感应蛋白 用内亲和素。这些研究的结果预计将推动目前对 突触生物学，并引领神经疾病的解决方案。

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.