Parkinson’s disease is a neurodegenerative disorder characterized by the loss of motor skills and cognitive impairment. The hallmark of this disease is the presence of Lewy bodies in the substantia nigra of the brain, where the accumulation of alpha-synuclein amyloid fibrils lead to the death of dopaminergic neurons. Understanding the factors influencing AS aggregation and developing effective strategies for its inhibition is of paramount importance for developing potential therapeutic interventions. Previous studies suggest that flavonoids in green and black tea have neuroprotective properties that decrease the fibrillization rate of AS. This thesis investigates the inhibitory effects of two flavonoids coming from green and black tea, namely: EGCG, TFDG, and HSA on AS aggregation, shedding light on their potential as therapeutic candidates.
The study employed a combination of biochemical and biophysical experimental techniques to elucidate the inhibitory mechanisms of EGCG, TFDG, and HSA on AS aggregation. Initial experiments involved the characterization of AS fibrillation kinetics using ThT assays, TEM, and CD. Results revealed that flavonoids exhibited similar inhibitory effects on AS aggregation, with more than 90% inhibitory potency. Interestingly, when aggregated AS was exposed to EGCG or TFDG, the amyloid fibrils changed conformation and formed non-toxic amorphous oligomers. The 13C-detected NMR experiments, adapted to probe the AS dynamic conformation and interactions at the atomic level at physiologically relevant conditions, further provided insights into the binding interactions between flavonoids and AS, revealing interaction with hydrophobic residues involved in the inhibition process.
Furthermore, the role of HSA, a major protein component of the blood plasma, in modulating α-synuclein aggregation in the presence of tea-derived flavonoids was investigated. The study demonstrated, in line with the previous reports, that HSA can significantly suppress AS fibrillation, and moreover, the presence of HSA further enhances the flavonoids’ inhibitory effect.
My findings provide valuable atomic level mechanistic insights into the inhibitory effects of EGCG and TFDG on alpha-synuclein aggregation. The comprehensive spectroscopic and biophysical investigation provides a solid foundation for further developing flavonoid-based inhibitors, subsequently drug candidates blocking the AS toxic oligomers formation and aggregation.
| Identifer | oai:union.ndltd.org:kaust.edu.sa/oai:repository.kaust.edu.sa:10754/693431 |
| Date | 07 1900 |
| Creators | Lozano Sandoval, Cecilia Alexandra |
| Contributors | Jaremko, Lukasz, Biological and Environmental Science and Engineering (BESE) Division, Chodasiewicz, Monika, Liberale, Carlo |
| Source Sets | King Abdullah University of Science and Technology |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Rights | 2024-08-03, At the time of archiving, the student author of this thesis opted to temporarily restrict access to it. The full text of this thesis will become available to the public after the expiration of the embargo on 2024-08-03. |
| Relation | N/A |
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