Elucidation of the Biochemical Mechanism and In Vivo Functions of Spastin

这个奖项的目的是完成我的培训，并建立一个高度跨学科的实验室， 在美国的学术机构，重点研究细胞骨架调节剂的作用机制。我的实验室 将采取全面的，多方面的方法，将原子分辨率结构信息与 在体外和细胞的更大背景下的单分子动力学。该奖项的研究重点是 剖析痉挛的生化和细胞机制。痉挛素基因的突变是导致 遗传性痉挛性截瘫的原因，一组知之甚少的神经退行性疾病 以轴突病变为特征。我已经发现痉挛素切断微管（Roll-Mecak和Vale， 2005年）。疾病突变损害切断，连接痉挛的微管细胞骨架的重塑， 神经变性这里概述的研究计划是高度跨学科的，整合技术和 从结构生物学，生物物理学和细胞生物学的概念来回答三个基本问题， spastin功能：1）spastin在整个ATP酶循环中的原子结构是什么，它如何结合和 破坏微管; 2）它如何利用ATP水解的能量来分解微管;以及 3)痉挛素如何影响活细胞中微管的结构和动力学， 当痉挛素耗尽或突变时会产生什么后果？尽管它对神经元的存活很重要 对痉挛素知之甚少。详细了解其机制和基本细胞生物学， 这对了解疾病的原因至关重要，这项建议提出了基本的机制， 这是进一步开发治疗方法所需的基础。微管微扰 动力学和结构已经成为各种神经退行性疾病的共同主题， 对痉挛素作用的理解将对所有这些疾病的病因学产生影响。 本研究的目的是了解一种酶，痉挛素的功能， 在大多数遗传性痉挛性截瘫患者中， 神经退行性疾病我发现痉挛会破坏细胞骨架的一个核心组成部分。 这项研究将为开发这组患者的治疗方法提供基础。 也增加了我们对其他神经退行性疾病的理解。

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.