Elucidation of the Biochemical Mechanism and In Vivo Functions of Spastin

这个奖项的目标是完成我的培训，并在一个 美国一家学术机构，专注于细胞骨架调节机制的研究。我的实验室 将采取全面、多方面的方法，将原子分辨率结构信息与 在体外和更大的细胞范围内的单分子动力学。该奖项的研究重点是 剖析痉挛蛋白的生化和细胞机制。痉挛蛋白基因的突变是主要的 遗传性痉挛截瘫的病因，一组鲜为人知的神经退行性疾病 以轴索病为特征的。我发现spastin切断了微管(Roll-Mecak和Vale， 2005)。疾病突变损害切断，将spastin对微管细胞骨架的重塑联系在一起 神经退行性变。这里概述的研究计划是高度跨学科的，整合了技术和 从结构生物学、生物物理学和细胞生物学的概念来回答关于 Spastin的功能：1)Spastin在其ATPase周期中的原子结构是什么，它是如何结合和 破坏微管；2)如何利用ATP水解的能量来分解微管； 3)痉挛蛋白如何影响活细胞中的微管结构和动力学？ 当spastin耗尽或突变时所产生的后果？尽管它对神经元存活很重要 人们对痉挛知之甚少。对其机制和基本细胞生物学的详细了解是 对于理解疾病的原因至关重要，这一提议建立了基本的机制 为进一步开发治疗方法所需的基础工作。微管微扰 动力学和建筑已成为各种神经退行性疾病和 对痉挛蛋白作用的了解将对所有这些疾病的病因产生影响。 这项研究的目的是了解一种酶，即痉挛蛋白的功能。 在大多数遗传性痉挛截瘫患者中存在缺陷，这是一组了解很少的患者 神经退行性疾病。我发现，spastin破坏了细胞骨架的一个中心组成部分。 这项研究将为开发这一群体的治疗方法提供所需的基本基础 同时也增加了我们对其他神经退行性疾病的了解。

The objective of this award is to complete my training and to establish a highly interdisciplinary lab at an academic institution in the U.S., focused on the study of the mechanism of cytoskeletal regulators. My lab will take a comprehensive, multifaceted approach by linking atomic resolution structural information with single molecule dynamics in vitro and in the larger context of the cell. The research focus of this award is to dissect the biochemical and cellular mechanisms of spastin. Mutations in the spastin gene are the leading cause of hereditary spastic paraplegias, a group of poorly understood neurodegenerative disorders characterized by axonopathy. I have discovered that spastin severs microtubules (Roll-Mecak and Vale, 2005). Disease mutations impair severing, linking spastin's remodelling of the microtubule cytoskeletonto neurodegeneration. The research plan outlined here is highly interdisciplinary, integrating techniques and concepts from structural biology, biophysics and cell biology to answer three fundamental questions about spastin function: 1) What is spastin's atomic structure throughout its ATPase cycle and how does it bind and break the microtubule; 2) How does it use the energy of ATP hydrolysis to disassemble the microtubule; and 3) How does spastin affect microtubule architecture and dynamics in the living cell and what are the cellular consequences incurred when spastin is depleted or mutated ? Despite its importance for neuronal survival very little is known about spastin. A detailed understanding of its mechanism and basic cell biology are critical to understanding the causes of the disease and this proposal sets the fundamental mechanistic groundwork that is needed to develop therapies further down the road. Perturbation of microtubule dynamics and architecture has emerged as a common theme in a variety of neurodegenerative diseases and an understanding of spastin's effects will have implications for the etiologies of all these disorders. Lay Summary: The goal of this research is to understand the function of an enzyme, spastin, that is defective in the majority of patients with hereditary spastitc paraplegias, a group of poorly understood neurodegenerative disorders. I discovered that spastin breaks a central component of the cell's skeleton. This research will provide the basic groundwork needed for the development of treatments for this group of disorders and also increase our understanding of other neurodegenerative disorders.