Abrupt aggregation of misfolded proteins is a hallmark of the large group of amyloid pathologies that include diabetes type 2, Alzheimer and Parkinson's diseases. Protein aggregation yields oligomers and fibrils, β-sheet-rich structures that exert cell toxicity. Microscopic examination of amyloid deposits reveals the presence of lipids membranes, which suggests that lipids can be involved in the process of pathogenic protein assembly. In this talk, I will discus how lipids can uniquely alter the aggregation rates of insulin and lysozyme, protein that are associated with diabetes type 2 and systemic amyloidosis, respectively. Specifically, we found that cardiolipin (CL), ceramide (CER), and sphingomyelin (SM) accelerate, phosphatidylcholine (PC) strongly inhibits, whereas phosphatidylserine (PS) has no effect on the rate of protein aggregation. Furthermore, lipids uniquely alter the secondary structure of both insulin and lysozyme aggregates. Furthermore, we found that insulin and lysozyme aggregates grown in the presence of CL, CER, SM, PS, and CL:PC mixtures exert significantly lower production of reactive oxygen species and mitochondrial dysfunction compared to protein aggregates grown in the lipid-free environment. These findings suggest that a change in the lipid composition of cell membranes, which is taken place upon neurodegeneration, may trigger the formation of toxic protein species that otherwise would not be formed.

Lipids uniquely alter rates of insulin aggregation and lower toxicity of amyloid aggregates

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