Membrane lipid composition and its physicochemical properties define cell vulnerability to aberrant protein oligomers

Increasing evidence suggests that the interaction of misfolded protein oligomers with cell membranes is a primary event resulting in the cytotoxicity associated with many protein misfolding diseases, including neurodegenerative disorders. We describe here the results of a study on the relative contributions to toxicity of the physicochemical properties of both protein oligomers and the cell membrane with which they interact. We modulated the membrane content of cholesterol and the ganglioside GM1 in SH-SY5Y cells exposed to two types of oligomers of the prokaryotic protein HypF-N displaying different ultrastructural and cytotoxicity properties, and to oligomers formed by the amyloid β peptide associated with Alzheimer's disease. The results reveal that the degree of toxicity of the oligomersic species results from a complex interplay between the structural and physicochemical features of both the oligomers and the cellular membrane.