Abstract
The conversion of peptides or proteins from their soluble native states into intractable amyloid deposits is associated with a wide range of human disorders. Misfolded protein oligomers formed during the process of aggregation have been identified as the primary pathogenic agents in many such conditions. Here, we show the existence of a quantitative relationship between the degree of binding to neuronal cells of different types of oligomers formed from a model protein, HypF-N, and the GM1 content of the plasma membranes. In addition, remarkably similar behavior is observed for oligomers of the Aβ42 peptide associated with Alzheimer’s disease. Further analysis has revealed the existence of a linear correlation between the level of the influx of Ca2+ across neuronal membranes that triggers cellular damage, and the fraction of oligomeric species bound to the membrane. Our findings indicate that the susceptibility of neuronal cells to different types of misfolded oligomeric assemblies is directly related to the extent of binding of such oligomers to the cellular membrane.
Highlights
IntroductionDisruption of lipid rafts appears to protect mature neurons against oligomer cytotoxicity[21] and alterations in the membrane distribution of GM1 and GM2 have recently been reported in the brains of patients suffering from Alzheimer’s disease[23]
We investigated the degrees of co-localization of the two different types of HypF-N oligomers with cell membranes using scanning confocal microscopy in cells with basal GM1 content (Fig. 1A)
In cells treated with 100 μg/ml GM1, and containing the highest concentration of GM1, the Pearson’s correlation coefficient (PCC) values were 0.68 ± 0.13 and 0.66 ± 0.06 for type A and type B oligomers, respectively, indicating that GM1-enriched cells displayed a higher ability to recruit either type of oligomer (Fig. 1A,B)
Summary
Disruption of lipid rafts appears to protect mature neurons against oligomer cytotoxicity[21] and alterations in the membrane distribution of GM1 and GM2 have recently been reported in the brains of patients suffering from Alzheimer’s disease[23]. The importance of GM1 in promoting amyloid aggregation and in modulating the interaction of aggregates with cell membranes and its associated role in mediating aggregate cytotoxicity, have been explored in some detail[24,25] It is not clear, whether a quantitative relationship exists between GM1 abundance on cell surfaces and the ability of the corresponding membranes to recruit protein oligomers and impair cell viability. This analysis shows that their biological effects are directly related to the quantity of oligomers bound to the membrane regardless of their sequence or structure, with their effects becoming similar when similar amounts of different oligomers are bound to the membrane
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