The hidden hand of lipids in the amyloid cascade

Abstract

Intrinsically disordered proteins (IDPs), such as amyloid polypeptide (IAPP), beta-amyloid (A\b{eta}), and {\alpha}-synuclein are linked to the insurgence of type 2 diabetes, Alzheimer's, and Parkinson's diseases, respectively. Common molecular mechanisms have been explored to elucidate the toxicity pathway of these proteins. For many years, the amyloid hypothesis was believed to explain the toxicity. According to this hypothesis, the misfolding of these proteins and the further aggregation into mature and insoluble fibrils rich in the \b{eta}-sheet lead to cell death. However, this theory fails to explain much of the experimental evidence, which led to the hypothesis of soluble small-oligomer toxicity and pore-like activity. Recently, the lipid-chaperone model was proposed to explain the effect of lipid compositions on IDPs toxicity in vitro. In this work, we summarize the different toxicity models and discuss the possible relevance of the lipid-chaperone model in a biological context, such as protein overexpression and lipid oxidation. Furthermore, we briefly explore how the model can be incorporated into the framework that explains IDPs toxicity, such as fibril formation and secondary nucleation.