The Division of Amyloid Fibrils: Systematic Comparison of Fibril Fragmentation Stability by Linking Theory with Experiments.

David M Beal,Mick F Tuite,Ricardo Marchante,Tracey J Purton,Wei-Feng Xue,Magali Tournus,David P Smith,Marie Doumic

doi:10.1016/j.isci.2020.101512

Abstract

SummaryThe division of amyloid protein fibrils is required for the propagation of the amyloid state and is an important contributor to their stability, pathogenicity, and normal function. Here, we combine kinetic nanoscale imaging experiments with analysis of a mathematical model to resolve and compare the division stability of amyloid fibrils. Our theoretical results show that the division of any type of filament results in self-similar length distributions distinct to each fibril type and the conditions applied. By applying these theoretical results to profile the dynamical stability toward breakage for four different amyloid types, we reveal particular differences in the division properties of disease-related amyloid formed from α-synuclein when compared with non-disease associated model amyloid, the former showing lowered intrinsic stability toward breakage and increased likelihood of shedding smaller particles. Our results enable the comparison of protein filaments' intrinsic dynamic stabilities, which are key to unraveling their toxic and infectious potentials.

Highlights

Amyloid fibrils, proteinaceous polymers with a cross-b core structure, represent an important class of bio-nanomaterials (Bleem and Daggett, 2017; Knowles and Buehler, 2011)
SUMMARY The division of amyloid protein fibrils is required for the propagation of the amyloid state and is an important contributor to their stability, pathogenicity, and normal function
By applying these theoretical results to profile the dynamical stability toward breakage for four different amyloid types, we reveal particular differences in the division properties of disease-related amyloid formed from asynuclein when compared with non-disease associated model amyloid, the former showing lowered intrinsic stability toward breakage and increased likelihood of shedding smaller particles

Summary

Introduction

Proteinaceous polymers with a cross-b core structure, represent an important class of bio-nanomaterials (Bleem and Daggett, 2017; Knowles and Buehler, 2011). Despite knowledge of its importance, it is not understood why amyloid division processes give rise to varied biological impacts ranging from normal propagation of functional amyloid assemblies to large inert structures or the creation of molecular species involved in disease, e.g., small cytotoxic amyloid species and infective prions, which are transmissible amyloid particles. In this respect, the resistance of amyloid to division is a critical aspect to protein misfolding associated with disease progression and biological roles of functional amyloid assemblies (e.g., Tanaka et al, 2006). It has been suggested that fibrils are not merely the end product of amyloid aggregation, but rather elicit profound biological responses through fibril fragmentation and oligomer shedding (Tipping et al, 2015), due to lack of fibril stability

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