Graduation Date

5-2021

Document Type

Master's Thesis

Degree

Master of Science

Program

Biological Science

Program Director

Meredith Protas, PhD

First Reader

Lisa Ellerby, PhD

Second Reader

Deena Emera, PhD

Abstract

Huntington’s Disease (HD) is a neurodegenerative disorder caused by a CAG expansion within exon 1 of the huntingtin gene. The mutated HTT (mHTT) protein aggregates and is proteolytically cleaved, forming toxic fragments of the protein that disrupt cellular homeostasis. Specifically, the striatum is particularly vulnerable, where progression of HD results in the loss of medium spiny neurons. There are no cures for this disease, and the therapeutic options currently available are more tailored towards symptom management. Previous studies our lab suggest that the alteration of kinases may be beneficial in treating HD (Zhang et al., 2012). Additional studies also done by our lab show that canonical striatal markers are disrupted as a result of mHTT expression (Ring et al., 2015). However, the role of the protein kinase C (PKC) family in HD pathology and how mHTT alters the developing striatum remain relatively unknown (Harris et al., 2001; Zemskov & Nukina, 2003).

This first chapter of this study pertains to experiments conducted in neural stem cell (NSC) and mouse models of HD. In these models, I describe altered expression of individual PKC isoforms in specific cell types and brain regions relevant to disease. I next found that treatment with Prostratin, a PKC activating molecule, prevents mHTT-associated toxicities, changes post-translational modifications of HTT, and potentially clears mHTT. In chapter 2, I found that transcription factors that aid in striatal development can be used to create organoids that model the striatum specifically. In the future, these organoids could be used as a model system to understand how mHTT affects the striatum before symptom onset and to investigate potential therapeutic targets. Together, this study yields new insight into PKC’s role in HD and its potential as a therapeutic target, and it provides the possibility of using a more humanized 3-dimensional model system to study changes in HD from the cellular to tissue level.

Available for download on Wednesday, May 31, 2023

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