Title

The role of amyloid oligomers in neurodegenerative pathologies

Publication Name

International Journal of Biological Macromolecules

Abstract

Many neurodegenerative diseases are rooted in the activities of amyloid-like proteins which possess conformations that spread to healthy proteins. These include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). While their clinical manifestations vary, their protein-level mechanisms are remarkably similar. Aberrant monomeric proteins undergo conformational shifts, facilitating aggregation and formation of solid fibrils. However, there is growing evidence that intermediate oligomeric stages are key drivers of neuronal toxicity. Analysis of protein dynamics is complicated by the fact that nucleation and growth of amyloid-like proteins is not a linear pathway. Feedback within this pathway results in exponential acceleration of aggregation, but activities exerted by oligomers and fibrils can alter cellular interactions and the cellular environment as a whole. The resulting cascade of effects likely contributes to the late onset and accelerating progression of amyloid-like protein disorders and the widespread effects they have on the body. In this review we explore the amyloid-like proteins associated with AD, PD, HD and ALS, as well as the common mechanisms of amyloid-like protein nucleation and aggregation. From this, we identify core elements of pathological progression which have been targeted for therapies, and which may become future therapeutic targets.

Open Access Status

This publication may be available as open access

Volume

181

First Page

582

Last Page

604

Funding Number

APP1135720

Funding Sponsor

National Health and Medical Research Council

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Link to publisher version (DOI)

http://dx.doi.org/10.1016/j.ijbiomac.2021.03.113