Year of Publication

2003

Document Type

Dissertation

College

Arts and Sciences

Department

Biology

First Advisor

Sheldon M. Steiner

Abstract

Polyglutamine expansion disorders are progressive neurodegenerative diseasesthat are caused by the pathological expansion of polyglutamine repeats. Huntington'sdisease (HD) is a polyglutamine disorder caused by the expansion of an existingpolyglutamine tract in a novel protein, Huntingtin (Htt). Oxidative stress has beenimplicated in the neural dysfunction observed in multiple neurodegenerative conditionsincluding HD. The tumor suppressor p53 is a multifunctional protein that has roles inthe cell cycle, apoptosis and neurodevelopment. The role of p53 in HD-associatedneurodegeneration has been studied but not fully elucidated, nor has the role of p53 inoxidative stress toxicity been fully elucidated.Here I present work that demonstrates polyglutamine expansion inducedalterations to p53 stability, localization, and activity. The transcriptional activity of p53was found to have a role in oxidative stress mediated as well as polyglutaminemediated neurotoxicity in vitro. The expression of p53 was also altered in vivo in amouse model of HD as well as in HD brain.Taken together, these data demonstrate a role for p53 in polyglutamine and oxidativestress toxicity.

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