A unifying framework for amyloid-mediated membrane damage: The lipid-chaperon hypothesis

TL;DR

This paper proposes a unifying lipid-chaperone hypothesis explaining how amyloidogenic proteins interact with membranes, contributing to membrane damage in diseases like Alzheimer's, Parkinson's, and diabetes, through molecular-level insights and combined experimental-computational approaches.

Contribution

It introduces a novel lipid-chaperone framework that unifies diverse mechanisms of amyloid-induced membrane damage and emphasizes the importance of lipid-protein complexes in disease pathology.

Findings

Lipid-protein complexes act as molecular switches in membrane interactions.

Early molecular events involve complex aggregation and pore formation processes.

A combined experimental and computational approach enhances understanding of amyloid-membrane interactions.

Abstract

Over the past thirty years, researchers have highlighted the role played by a class of proteins or polypeptides that forms pathogenic amyloid aggregates in vivo, including i) the amyloid Abeta peptide, which is known to form senile plaques in Alzheimer's disease; ii) alpha-synuclein, responsible for Lewy body formation in Parkinson's disease and iii) IAPP, which is the protein component of type 2 diabetes-associated islet amyloids. These proteins, known as intrinsically disordered proteins (IDPs), are present as highly dynamic conformational ensembles. IDPs can partially (mis) fold into (dys) functional conformations and accumulate as amyloid aggregates upon interaction with other cytosolic partners such as proteins or lipid membranes. In addition, an increasing number of reports link the toxicity of amyloid proteins to their harmful effects on membrane integrity. Still, the molecular mechanism underlying the amyloidogenic proteins transfer from the aqueous environment to the hydrocarbon core of the membrane is poorly understood. This review starts with a historical overview of the toxicity models of amyloidogenic proteins to contextualize the more recent lipid-chaperone hypothesis. Then, we report the early molecular-level events in the aggregation and ion-channel pore formation of Abeta, IAPP, and alpha-synuclein interacting with model membranes, emphasizing the complexity of these processes due to their different spatial-temporal resolutions. Next, we underline the need for a combined experimental and computational approach, focusing on the strengths and weaknesses of the most commonly used techniques. Finally, the last two chapters highlight the crucial role of lipid-protein complexes as molecular switches among ion-channel-like formation, detergent-like, and fibril formation mechanisms and their implication in fighting amyloidogenic diseases.