Regulation of Microtubule-based Membrane Traffic by Septin GTPases

项目摘要 膜细胞器和大分子的长距离运输缺陷是其发病机制的基础。 以及许多疾病的进展，包括神经退行性疾病、精神发育迟滞和创伤 脑部受伤。长距离转运沿微管(MT)细胞骨架发生，并由 激动素和动力蛋白马达。了解MT依赖的转运机制对于 旨在减轻与运输阻塞相关的神经毒性的治疗方法的开发。尽管 尽管取得了许多进展，但在很大程度上仍不清楚长距离传输在空间和时间上受到多大程度的控制。 这是我们在细胞生物学知识上的一个根本差距，并影响了对许多基本知识的理解 过程包括神经元蛋白质如何通过几何复杂的细胞骨架并到达其 轴突和树突中的适当目的地。空间调节需要调节MT电机的活动 以及它们与MTS的相互作用。值得注意的是，MT现在被认为通过与MT相关的方式提供指导线索 蛋白质(MAP)和微管蛋白修饰，影响MT发动机及其货物的行程。了解以下内容 然而，这些基于MT的指导线索是相当有限的，并且空间控制的基础机制 对MT依赖的运输机制知之甚少。该项目的长期目标是了解MT- 依赖的转运由Septins调节，Septins是一种与MTS相关的GTP结合蛋白家族。我们的 初步数据表明，Septins直接调节MT-Kinesin的相互作用，影响 海马神经元中的激动素和货币体。在这里，我们将研究Septins的这一前所未有的功能， 对Septins包含膜空间引导的新调节模块的假设进行检验 堵车。基于正在进行的工作，我们将使用细胞生物学和体外无细胞方法来 从机制上决定：1)间隔蛋白如何控制神经细胞膜的运输；2)运动蛋白的运动性 马达受MT相关的Septins的调控。我们的研究将为空间调控提供新的见解。 对MT依赖的转运和Septins的神经元功能的影响，它们在 神经和精神障碍。从长远来看，我们的研究将为新的治疗方法铺平道路 旨在恢复患病神经元中MT依赖的运输的策略。

Project Summary Defects in the long-range transport of membrane organelles and macromolecules underlie the pathogenesis and progression of many diseases including neurodegenerative disorders, mental retardation and traumatic brain injury. Long-range transport takes place along the microtubule (MT) cytoskeleton and is driven by the kinesin and dynein motors. Understanding the mechanisms of MT-dependent transport is essential for the development of therapies that aim to alleviate the neurotoxicity associated with transport blockages. Despite many advances, it remains largely unknown how long-range transport is spatially and temporally controlled. This is a fundamental gap in our knowledge of cell biology and impacts understanding of many fundamental processes including how neuronal proteins navigate a geometrically complex cytoskeleton and reach their proper destinations in axons and dendrites. Spatial regulation requires modulation of the activity of MT motors and their interaction with MTs. Notably, MTs are now thought to provide guidance cues through MT-associated proteins (MAPs) and tubulin modifications, affecting the itinerary of MT motors and their cargo. Knowledge of these MT-based guidance cues, however, is rather limited and the mechanisms underlying the spatial control of MT-dependent transport are little understood. The long-term goal of this project is to understand how MT- dependent transport is regulated by septins, a family of GTP-binding proteins that associate with MTs. Our preliminary data demonstrate that septins directly modulate MT-kinesin interactions, affecting the transport of kinesins and cargo in hippocampal neurons. Here, we will investigate this unprecedented function of septins, testing the hypothesis that septins comprise a novel regulatory module for the spatial guidance of membrane traffic. Based on work in progress, we will use cell biological and in vitro cell-free approaches to mechanistically determine: 1) how septins control neuronal membrane traffic, and 2) how the motility of kinesin motors is regulated by MT-associated septins. Our studies will provide new insights into the spatial regulation of MT-dependent transport and the neuronal functions of septins, which are abnormally expressed in neurological and psychiatric disorders. In the long-term, our studies will pave the way to new therapeutic strategies that aim to restore MT-dependent transport in diseased neurons.