Biology

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Browsing Biology by Author "Alshehabi, Yasmeen"

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    Restoring p62 Palmitoylation as a Viable Therapeutic Approach for Mitigating the Effects of Huntington Disease
    (University of Waterloo, 2025-04-22) Alshehabi, Yasmeen
    Huntington disease (HD) is a devastating neurodegenerative disorder marked by motor impairment and cognitive decline, ultimately leading to death. HD is caused by an expanded cytosine-adenine-guanine (CAG) repeat in the huntingtin (HTT) gene, which codes for a polyglutamine expansion that confers toxic effects to the mutant huntingtin (mHTT) protein. These effects include the toxic aggregation of mHTT and the dysfunction of mHTT as a scaffold in autophagy, both of which disrupt autophagy in HD. Autophagy involves the loading of cargo into autophagosomes, which fuse with lysosomes for degradation of its contents. In HD, the cargo-loading step, in which sequestosome 1 (p62, SQSTM-1) and HTT deliver cargo to microtubule-associated protein 1 light chain 3 (LC3) located on the autophagosome membrane, is deficient, leading to an accumulation of empty autophagosomes. This deficiency may be linked to reduced mHTT and p62 palmitoylation, since palmitoylation is a reversible post-translational modification (PTM) that plays an important role in the regulation of protein trafficking to and from membranes. However, our focus is on p62, the main cargo-loading adaptor protein. The Martin group has confirmed that p62 is palmitoylated, and its palmitoylation is reduced in the brains of HD patients and mouse models. Therefore, the identification of a small molecule that increases p62 palmitoylation holds therapeutic promise for HD, rescuing cargo-loading and reducing mHTT aggregation and toxicity. A high-throughput screening of FDA-approved drugs identified blood-brain barrier permeable Vorinostat as a potential candidate to increase p62 palmitoylation. The objectives of this project are to investigate the function of Vorinostat and assess its effectiveness as a therapeutic for HD. Through the work described in this thesis, I have confirmed that Vorinostat increases p62 palmitoylation and enhances autophagy. Furthermore, I have suggested that Vorinostat may be working as both a depalmitoylation and deacetylation inhibitor to increase p62 palmitoylation. In addition, I have expanded the characterization of the YAC128 transgenic HD mouse model, examining body weight, food intake, motor function, anxiety, respiration, and energy expenditure. A comprehensive understanding of this HD mouse model is essential before advancing to preclinical studies. Finally, I have explored potential overlaps in the palmitoylation of proteins implicated in HD and ALS pathogenesis. Given the critical role of palmitoylation, elucidating and targeting its dysregulation in disease using small molecules like Vorinostat presents a viable therapeutic strategy for mitigating pathogenesis. Consequently, Vorinostat is a promising candidate for HD and warrants further evaluation in preclinical trials.