Amyloid Fibrillation of the Glaucoma Associated Myocilin Protein is Inhibited by Epicatechin Gallate (ECG)

Overview

Journal RSC Adv

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2022 Nov 2

PMID 36320765

Authors

Ritika Sharma

Anchala Kumari

Bishwajit Kundu

Abhinav Grover

Affiliations

Soon will be listed here.

Abstract

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.

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