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Molecular control of synaptobrevin retrieval and its biological function by synaptophysin

突触素修复突触短蛋白的分子控制及其生物学功能

基本信息

批准号：
BB/L019329/1
负责人：
Michael Cousin
金额：
$ 51.65万
依托单位：
University of Edinburgh
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FL019329%2F1
关键词：
Molecular control synaptobrevin retrieval its

项目摘要

Brain cells (neurones) communicate by releasing chemical neurotransmitters. Neurotransmitters are stored in small spherical compartments within neurones called synaptic vesicles (SVs). When neurones communicate, SVs fuse with the outer surface of the neurone causing neurotransmitter release. After neurotransmitter release these SVs are reformed by a process called endocytosis. The correct formation of SVs during endocytosis is essential for the maintenance of neurotransmitter release, since SVs with the wrong composition will be faulty for subsequent fusion. A critical part of SV generation is the packaging the correct proteins in the correct amounts into SVs. This is usually done by specific molecules called adaptor proteins, however in some cases additional molecules are required. We have recently identified an essential role for the protein synaptophysin in coordinating the packaging of sybII into SVs during endocytosis. While these proteins are known to stick to each other, no-one knows which regions of the proteins are important for this. Other molecules are also suggested to be required to control sybII and synaptophysin packaging into SVs. These are AP180 and AP-2. We have proposed a working model whereby all four proteins stick together in a coordinated manner to control packaging of sybII and synaptophysin into SVs. This model will be tested in this application. Finally various different types of syb are found on SVs, all of which have specific jobs in the control of neurotransmitter release. Therefore synaptophysin may also control their packaging into SVs and subsequently their biological role. We propose that synaptophysin is the central organiser in the packaging of different syb molecules into SVs during endocytosis. We will test this by a number of approaches. We will examine how syb movements differ when the gene encoding synaptophysin is removed from neurones grown on glass coverslips. We will also examine the simultaneous movement of altered forms of sybs and synaptophysin which do not stick to each other to see how their interaction controls their function. We will also monitor syb and synaptophysin movement in the absence of AP180 or AP-2. Finally we will determine how interfering with the normal function of synaptophysin in syb retrieval alters neurotransmitter release by detecting it indirectly via electrical changes in neighbouring neurones. The combination of experiments outlined in this application will systematically dissect the role of synaptophysin in both the control of the packaging of different sybs into SVs but also its downstream functions in neurotransmitter release. This is very important, since a decrease in the efficiency of syb packaging into SVs is proposed to underlie a series of neurodegenerative and neurodevelopmental disorders such as Alzheimer's Disease, Parkinson's Disease and X-linked intellectual disability. It will also provide important leads outside this field, since the mutants created in this application can be used to examine other possible neuronal functions of synaptophysin such as the formation of connections between neurones in brain.

脑细胞（神经元）通过释放化学神经递质进行交流。神经递质储存在神经元内称为突触小泡 (SV) 的小球形隔室中。当神经元进行交流时，SV 与神经元的外表面融合，导致神经递质释放。神经递质释放后，这些 SV 通过称为内吞作用的过程进行重组。胞吞过程中 SV 的正确形成对于维持神经递质释放至关重要，因为组成错误的 SV 将会导致后续的融合出现问题。 SV 生成的一个关键部分是将正确数量的正确蛋白质包装到 SV 中。这通常是通过称为衔接蛋白的特定分子来完成的，但在某些情况下需要额外的分子。我们最近发现了突触素蛋白在内吞过程中协调 sybII 包装到 SV 中的重要作用。虽然已知这些蛋白质会相互粘附，但没有人知道蛋白质的哪些区域对此很重要。还建议需要其他分子来控制 sybII 和突触素包装到 SV 中。它们是 AP180 和 AP-2。我们提出了一种工作模型，所有四种蛋白质以协调的方式粘在一起，以控制 sybII 和突触素包装到 SV 中。该模型将在此应用程序中进行测试。最后，在 SV 上发现了各种不同类型的 syb，所有这些 syb 在控制神经递质释放方面都有特定的作用。因此，突触素也可能控制它们包装到 SV 中，并随后控制它们的生物学作用。我们认为突触素是胞吞过程中将不同 syb 分子包装成 SV 的中心组织者。我们将通过多种方法对此进行测试。我们将研究当编码突触素的基因从玻璃盖玻片上生长的神经元中去除时，syb 运动有何不同。我们还将检查不同形式的 syb 和突触素的同时运动，它们不会相互粘附，以了解它们的相互作用如何控制它们的功能。我们还将在没有 AP180 或 AP-2 的情况下监测 syb 和突触素运动。最后，我们将通过邻近神经元的电变化间接检测突触素的正常功能，从而确定干扰syb检索中突触素的正常功能如何改变神经递质的释放。本申请中概述的实验组合将系统地剖析突触素在控制不同sybs包装成SVs以及其在神经递质释放中的下游功能中的作用。这非常重要，因为 syb 包装成 SV 的效率降低被认为是一系列神经退行性和神经发育障碍的基础，例如阿尔茨海默病、帕金森病和 X 连锁智力障碍。它还将提供该领域之外的重要线索，因为在该应用中创建的突变体可用于检查突触素的其他可能的神经元功能，例如大脑中神经元之间连接的形成。