Membrane Curvature Sensing Mechanisms for Synaptic Vesicle Endocytosis

项目概要 内吞作用在支持人脑健康方面发挥着至关重要的作用。从功能上讲，突触小泡 内吞作用使神经元能够维持突触传递而不耗尽突触的供应 囊泡。从结构上讲，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会造成神经传递缺陷，从而导致广泛的神经传递缺陷 神经系统疾病和精神疾病。这项研究的长期目标是确定内吞作用如何 蛋白质协同作用以支持突触内吞作用的多种途径。来自多个实验室的工作 包括我自己的发现，曲率感应蛋白内亲蛋白在突触中起着至关重要的作用 囊泡内吞作用。在本提案中，我们将研究曲率传感机制引导的假设 内吞蛋白以多种内吞途径发挥其功能。我们提出三个具体目标。 1）我们将确定曲率传感基序在体内的作用。我们专注于曲率传感 内亲蛋白的两亲性螺旋，因为它对于突触小泡内吞作用至关重要。 2）我们将研究如何 曲率信号被下游蛋白 synaptojanin 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 不依赖内皮素的内吞作用机制，这是一个缺乏分子信息的领域。通过一个 通过无偏见的遗传筛选，我们发现了另一种在平行途径中起作用的曲率传感蛋白 与内亲素。这些研究的结果预计将突破当前知识的界限 突触生物学并找到神经系统疾病的解决方案。

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.