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Abstract #106240 Published in IGR 23-3
Amyloid fibrillation of the glaucoma associated myocilin protein is inhibited by epicatechin gallate (ECG)
Sharma R; Kumari A; Kundu B; Grover ARSC advances 2022; 12: 29469-29481
Inherited glaucoma is a recent addition to the inventory of diseases arising due to protein misfolding. Mutations in the olfactomedin (OLF) domain of myocilin are the most common genetic cause behind this disease. Disease associated variants of m-OLF are predisposed to misfold and aggregate in the trabecular meshwork (TM) tissue of the eye. In recent years, the nature of these aggregates was revealed to exhibit the hallmarks of amyloids. Amyloid aggregates are highly stable structures that are formed, often with toxic consequences in a number of debilitating diseases. In spite of its clinical relevance the amyloidogenic nature of m-OLF has not been studied adequately. Here we have studied the amyloid fibrillation of m-OLF and report ECG as an inhibitor against it. Using biophysical and biochemical assays, coupled with advanced microscopic evaluations we show that ECG binds and stabilizes native m-OLF and thus prevents its aggregation into amyloid fibrils. Furthermore, we have used REMD simulations to delineate the stabilizing effects of ECG on the structure of m-OLF. Collectively, we report ECG as a molecular scaffold for designing and testing of novel inhibitors against m-OLF amyloid fibrillation.
School of Biotechnology, Jawaharlal Nehru University New Delhi-110067 India sharma.ritika198@gmail.com abhinavgr@gmail.com +91-8130738032.
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