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发病机制的基础 和许多疾病的进展，包括神经退行性疾病、精神发育迟滞和创伤性 脑损伤长距离转运发生沿着微管（MT）细胞骨架，并由 驱动蛋白和动力蛋白马达。了解MT依赖性转运的机制对于 开发旨在减轻与转运阻滞相关的神经毒性的疗法。尽管 尽管取得了许多进展，但远距离迁移在空间和时间上是如何受到控制的，这在很大程度上仍然是未知的。 这是我们对细胞生物学知识的一个根本性空白，并影响了对许多基本知识的理解。 过程包括神经元蛋白如何导航几何复杂的细胞骨架，并达到其 在轴突和树突中有合适的目的地空间调节需要调制MT运动的活动 以及他们与MT的互动。值得注意的是，MT现在被认为通过MT相关的 蛋白质（地图）和微管蛋白的修改，影响行程的MT马达和他们的货物。知识 然而，这些基于MT的引导提示是相当有限的，并且空间控制的潜在机制 对MT依赖性转运的了解很少。该项目的长期目标是了解MT- 依赖性转运受septins调节，septins是与MT相关的GTP结合蛋白家族。我们 初步数据表明，septins直接调节MT-驱动蛋白的相互作用， 海马神经元中的驱动蛋白和货物。在这里，我们将研究这种前所未有的功能septins， 检验septins包含用于膜的空间引导的新的调节模块的假设 交通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， 机械地确定：1）septins如何控制神经元膜交通，以及2）驱动蛋白的运动性如何影响神经元膜交通。 电机由MT相关隔膜调节。我们的研究将为空间调控提供新的见解 MT依赖性运输和septins的神经功能，这是异常表达， 神经和精神疾病。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依赖性转运的策略。

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.