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Abstract

Grant Number:	1K99NS057934-01
Project Title:	Elucidation of the Biochemical Mechanism and In Vivo Functions of Spastin

PI Information:	Name	Email	Title
	ROLL-MECAK, ANTONINA	rolla@cmp.ucsf.edu

Abstract: DESCRIPTION (provided by applicant): 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 remodeling of the microtubule cytoskeleton to 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 spastic 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.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
microtubule
X ray crystallography, analog, base, biochemistry, biophysics, cell, cell biology, cell component, chemical, concept, cue, culture, cytoskeleton, electron crystallography, electron microscopy, emotion, enzyme, family, fluorescence, gene, gene mutation, hydrolysis, intracellular transport, lead, lighting, measurement, model, mutant, neural degeneration, neuron, paraplegia, particle, phenotype, protein, sectioning, structural biology, therapy, training, work site

Institution:	UNIVERSITY OF CALIFORNIA SAN FRANCISCO
	3333 California St., Ste 315
	SAN FRANCISCO, CA 941430962
Fiscal Year:	2007
Department:	CELLULAR & MOLECULAR PHARMACOLOGY (CMP)
Project Start:	01-DEC-2006
Project End:	30-NOV-2008
ICD:	NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG:	ZNS1

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