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Misfolded protein oligomers: mechanisms of formation, cytotoxic effects, and pharmacological approaches against protein misfolding diseases.

Published version
Peer-reviewed

Repository DOI


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Authors

Rinauro, Dillon J 
Chiti, Fabrizio 
Vendruscolo, Michele 

Abstract

The conversion of native peptides and proteins into amyloid aggregates is a hallmark of over 50 human disorders, including Alzheimer's and Parkinson's diseases. Increasing evidence implicates misfolded protein oligomers produced during the amyloid formation process as the primary cytotoxic agents in many of these devastating conditions. In this review, we analyze the processes by which oligomers are formed, their structures, physicochemical properties, population dynamics, and the mechanisms of their cytotoxicity. We then focus on drug discovery strategies that target the formation of oligomers and their ability to disrupt cell physiology and trigger degenerative processes.

Description

Acknowledgements: We would like to thank Dr. Alexander Dear and Dr. Laila Sakhnini for their invaluable feedback and academic insight.


Funder: Centre for Misfolding Diseases


Funder: DEVCOM-ARL

Keywords

Aggregation kinetics, Amyloid toxicity, Biophysics, Cellular interactions, Diagnostics, Drug discovery, Fibril fragmentation, Lecanemab, Protofibrils, Secondary nucleation, Therapeutics, Humans, Amyloid, Parkinson Disease, Proteostasis Deficiencies, Amyloid beta-Peptides

Journal Title

Mol Neurodegener

Conference Name

Journal ISSN

1750-1326
1750-1326

Volume Title

19

Publisher

Springer Science and Business Media LLC
Sponsorship
Horizon Europe UKRI Underwrite Innovate (10059436)
UKRI 10059436 and UKRI 10061100