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Abstract

Grant Number:	1R03MH076348-01
Project Title:	Aggregation and Clearance of Mutant Huntingtin(RMI)

PI Information:	Name	Email	Title
	ROTHMAN, JAMES E.	jr2269@columbia.edu	VICE CHAIRMAN

Abstract: DESCRIPTION (provided by applicant): Accumulation and aggregation of mutant proteins are a common link across a wide array of neurodegenerative disorders. Recently, an exciting theme has emerged: if mutant protein accumulation is eliminated, symptomatic progression not only halts but also leads to recovery from disease. The first indication that neurodegenerative diseases are reversible comes from an inducible mouse model of the polyglutamine disorder Huntington's disease (HD). In the presence of expanded polyglutamine huntingtin, mice recapitulated HD-like symptoms. When mutant gene expression was abolished, not only did the aggregates disappear, the symptoms regressed. These findings signal that neurodegenerative diseases need no longer be considered a death sentence. Unfortunately, however, the pathway underlying clearance of these mutant proteins are not yet clear. We believe that screening a well-designed cell-based assay with a chemical compound library will allow us to not only further clarify which degradative pathway is important, but may also reveal new means by which these pathways can be activated. We have therefore designed a functional cell-based assay that monitors not only aggregation of mutant huntingtin protein, but also its clearance. To do so, we created a stable cell line that conditionally expresses the N-terminus of huntingtin protein with polyQ proteins of different polyQ lengths fused to variants of GFP. These cell lines permit high throughput confocal microscopy to examine the state of the expressed mutant protein in live cells. We hypothesize that by eliminating the accumulated protein we will bring about recovery of the neurodegenerative process, as shown in several animal models of the disease.

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

Thesaurus Terms:
Huntington's disease, gene mutation, nerve /myelin protein, protein degradation
chemical aggregate, homopeptide, protein protein interaction
cell line, confocal scanning microscopy, green fluorescent protein, high throughput technology, peptide library

Institution:	COLUMBIA UNIVERSITY HEALTH SCIENCES
	Columbia University Medical Center
	NEW YORK, NY 100323702
Fiscal Year:	2005
Department:	PHYSIOLOGY AND CELLULAR BIOPHYSICS
Project Start:	16-SEP-2005
Project End:	15-SEP-2006
ICD:	NATIONAL INSTITUTE OF MENTAL HEALTH
IRG:	ZMH1

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