Date of Award
8-16-2024
Document Type
Open Access Thesis
Department
Biomedical Science
First Advisor
Norma Frizzell
Abstract
Neurodegenerative diseases, including Amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease, profoundly impact the brain and nervous system. In 2019, the United States reported the highest global prevalence of neurological disorders. This thesis approaches neurodegenerative diseases by emphasizing the critical role of a well-maintained antioxidant system, its intricate relationship with dietary patterns, and proposes an alternative fate of the antioxidant urate.
Neurodegenerative disease pathogenesis involves a complex interplay of neuroinflammation, mitochondrial dysfunction, misfolded proteins, and oxidative stress. Oxidative stress arises from an imbalance in the antioxidant defense system and the production of reactive oxygen species. Synergistic antioxidant interactions are vital for neuroprotection, ensuring the maintenance of each antioxidant in its reduced state.
Despite inconsistent results in clinical trials evaluating dietary patterns and antioxidant intake on neurodegenerative disease, some studies indicate a reduced risk of Parkinson’s Disease with higher α-tocopherol intake. Notably, antioxidant supplements like glutathione and coenzyme Q10 have not yielded improvements. Encouragingly, the Mediterranean diet and combination-supplements (omega-3s with α-tocopherol) have shown positive effects in reducing risk and progression, emphasizing the multifaceted nature of neuroprotection.
Additionally, lower urate levels correlate with severe clinical progression in neurodegenerative diseases. However, recent studies elevating urate to normal levels failed to demonstrate clinical benefits. Thus, urate's role in neurodegenerative disease requires further investigation. Based on the examination of recent literature evaluating novel actions of urate, this thesis aims to propose an alternative relationship between neurodegenerative diseases and urate.
Lower urate levels may reflect increased oxidative uratylation coupled with the formation of uratylated proteins. Neuroinflammation promotes the oxidation of urate resulting in an accumulation of urate radicals and other highly reactive urate electrophiles. This persists in an environment without sufficient antioxidants to reduce urate radicals. The formed urate electrophiles yield a bicyclic imidazolone that covalently attaches to an amino group of lysine in proteins, resulting in uratylated lysine. Consequently, we propose that protein function is altered, oxidative stress is increased, contributing to neurodegeneration. This explains why urate levels are lower in neurodegenerative diseases and are associated with worse clinical outcomes. This new viewpoint may help to improve early diagnosis and identify therapeutic studies.
Rights
© 2024, Elena Kelety
Recommended Citation
Kelety, E.(2024). Modulation of Neurodegenerative Disease Progression by Antioxidant Status. (Master's thesis). Retrieved from https://scholarcommons.sc.edu/etd/7691