Date of Graduation
Spring 2024
Degree
Master of Science in Chemistry
Department
Chemistry and Biochemistry
Committee Chair
Tuhina Banerjee
Abstract
ABSTRACT
The Protein misfolding and aggregation of alpha-synuclein (α-syn) into neurotoxic amyloids underlies the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). 4-Phenylbutyrate (PBA), an FDA drug approved for treating urea cycle disorders, has garnered significant attention as a potential chemical chaperone for targeting alpha-synuclein (α-syn) aggregation. Using in vitro assays, we demonstrated that PBA treatment alters the pattern of α-syn aggregation, as evidenced by reduced formation of oligomeric species and its increased susceptibility to proteolytic cleavage under the influence of PBA. Proteinase K assay, surface plasmon resonance, and Nile red studies indicate that PBA interacts with the extensive hydrophobic contacts of α-syn oligomers and significantly reduces α-syn-amyloid induced toxicity, suggesting that oligomerization may be a requirement for α-syn to exert its neurotoxic effect. Furthermore, using Thioflavin T based assays, we elucidated the kinetics of PBA-mediated inhibition of α-syn aggregation, highlighting its role in accelerating the maturation of α-syn fibrils. Current evidence both in vivo and in vitro suggests that α-syn oligomers exert the most neurotoxic effects. Current evidence both in vivo and in vitro suggests that α-syn oligomers exert the most neurotoxic effects. PBA preferential interaction with α-syn oligomers explains its ability to mitigate α-syn-induced cytotoxicity as observed in this study. Collectively, our findings provide compelling evidence for the neuroprotective potential of PBA in targeting protein misfolding and aggregation in PD and suggests an avenue for disease-modifying interventions in neurodegenerative disorders.
Keywords
α - synuclein, amyloid protein, fibrillation, neurodegenerative disorders, oligomers, 4-phenyl butyric acid, Thioflavin T assay
Subject Categories
Amino Acids, Peptides, and Proteins | Chemical Actions and Uses | Inorganic Chemicals | Medicinal-Pharmaceutical Chemistry
Copyright
© Kristos Awuah Baffour
Recommended Citation
Baffour, Kristos Awuah, "The Kinetic Modulation of α - Synuclein Fibrillation and Toxicity by 4-Phenylbutyric Acid" (2024). MSU Graduate Theses. 3979.
https://bearworks.missouristate.edu/theses/3979
Open Access
Included in
Amino Acids, Peptides, and Proteins Commons, Chemical Actions and Uses Commons, Inorganic Chemicals Commons, Medicinal-Pharmaceutical Chemistry Commons
