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- W2900348085 abstract "Oligomerization of γ-Synuclein is known to have implications for both neurodegeneration and cancer. Although it is known to co-exist with the fibrillar deposits of α-Synuclein (Lewy bodies), a hallmark in Parkinson's disease (PD), the effect of potential therapeutic modulators on the fibrillation pathway of γ-Syn remains unexplored. By a combined use of various biophysical tools and cytotoxicity assays we demonstrate that the flavonoid epigallocatechin-3-gallate (EGCG) significantly suppresses γ-Syn fibrillation by affecting its nucleation and binds with the unstructured, nucleus forming oligomers of γ-Syn to modulate the pathway to form α-helical containing higher-order oligomers (~158 kDa and ~ 670 kDa) that are SDS-resistant and conformationally restrained in nature. Seeding studies reveal that these oligomers although on-pathway in nature, are kinetically retarded and rate-limiting species that slows down fibril elongation. We observe that EGCG also disaggregates the protofibrils and mature γ-Syn fibrils into similar SDS-resistant oligomers. Steady-state and time-resolved fluorescence spectroscopy and isothermal titration calorimetry (ITC) reveal a weak non-covalent interaction between EGCG and γ-Syn with the dissociation constant in the mM range (Kd ~ 2-10 mM). Interestingly, while EGCG-generated oligomers completely rescue the breast cancer (MCF-7) cells from γ-Syn toxicity, it reduces the viability of neuroblastoma (SH-SY5Y) cells. However, the disaggregated oligomers of γ-Syn are more toxic than the disaggregated fibrils for MCF-7cells. These findings throw light on EGCG-mediated modulation of γ-Syn fibrillation and suggest that investigation on the effects of such modulators on γ-Syn fibrillation is critical in identifying effective therapeutic strategies using small molecule modulators of synucleopathies." @default.
- W2900348085 created "2018-11-16" @default.
- W2900348085 creator A5025774960 @default.
- W2900348085 creator A5058646356 @default.
- W2900348085 date "2018-12-20" @default.
- W2900348085 modified "2023-10-12" @default.
- W2900348085 title "Suppression, disaggregation, and modulation of γ‐Synuclein fibrillation pathway by green tea polyphenol EGCG" @default.
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- W2900348085 doi "https://doi.org/10.1002/pro.3549" @default.
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