Lipids reverse supramolecular chirality and reduce toxicity of amyloid fibrils

Abrupt aggregation of misfolded proteins is a hallmark of many medical pathologies including diabetes type 2, Alzheimer and Parkinson diseases. This results in the formation of amyloid fibrils, protein aggregates with distinct supramolecular chirality. A growing body of evidence suggests that lipids can alter rates of protein aggregation. In this study, we investigated whether lipids could alter the supramolecular chirality of amyloid fibrils. We found that if present at the stage of protein aggregation, phospho‐ and sphingolipids uniquely reversed supramolecular chirality of insulin and lysozyme fibrils. Furthermore, amyloid fibrils with opposite supramolecular chirality exerted distinctly different cell toxicity. Specifically, insulin and lysozyme fibrils with reversed supramolecular chirality were less toxic to cells than the aggregates with normal supramolecular chirality. These findings point on the important role of lipids and supramolecular chirality of amyloid fibrils in the onset and progression of amyloid diseases. We discovered that phospho‐ and sphingolipids uniquely reversed supramolecular chirality of insulin and lysozyme fibrils. We also found that amyloid fibrils with opposite supramolecular chirality exerted distinctly different cell toxicity. These findings demonstrate that lipids play critically important role in supramolecular chirality of amyloid fibrils and the onset and progression of amyloid diseases.