Graduation Date

5-2020

Document Type

Master's Thesis

Degree

Master of Science

Program

Biological Science

Program Director

Meredith Protas, PhD

First Reader

Lisa M. Ellerby, PhD

Second Reader

Kiowa Bower, PhD

Abstract

Huntington’s disease (HD) is a rare and incurable autosomal neurodegenerative disease affecting 1-10 in every 100,000 people in the world. There is no cure for HD and treatments available alleviate certain symptoms for short periods of time. Evidence suggests that neuropathology of HD begins with the proteolysis of the mutated Huntingtin (mHTT) protein. A variety of proteases, like the matrix metalloproteases, cleave mHTT creating proteinaceous fragments that are thought to be neurotoxic. As these fragments increase in the brain, the damage to neurons also increases, leading to chronic inflammation due to hyper reactive microglia and astrocytes attempting to minimize and repair damages. There are many potential avenues to treat HD and, in this study, we provide insight on regulating proteolytic dysfunction with the systemic introduction of endogenous tissue inhibitor for metalloproteases-2 (TIMP2). In addition, we suppress inflammation in a selective manner with compound MW151 in order to attenuate the increasing levels of pro-inflammatory markers and reactive gliosis in HD.

Available for download on Thursday, June 01, 2023

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