Tannic Acid Inhibits α-Synuclein Amyloid Fibril Formation via Binding to the Monomer N-terminal Domain

Abstract

α-Synuclein (αS) is an intrinsically disordered protein (IDP) that aggregates into amyloid fibrils during the progression of Parkinson’s Disease and other synucleinopathies. The N-terminal domain (residues 1-60) is now understood to play a critical role in the initial nucleation of aggregation, as well as a pivotal role in the monomer-fibril interaction underlying amyloid seeding. Here we report on the interaction between αS and the polyphenol tannic acid (TA), where a combination of solution NMR, atomic force microscopy (AFM), and ThT assays have identified that TA targets the aS N-terminal domain to inhibit amyloid fibril formation in a pH dependent manner. This work highlights the importance of targeting the N-terminus of aS to arrest fibril formation, and suggests the importance of including polyphenolic moieties in future amyloid inhibitors.