Quantitative Measurement of the Affinity of Toxic and Nontoxic Misfolded Protein Oligomers for Lipid Bilayers and of its Modulation by Lipid Composition and Trodusquemine

Many neurodegenerative diseases are associated with the self-assembly of peptides and proteins into fibrillar aggregates. Soluble misfolded oligomers formed during aggregation process, or released by mature fibrils, play a relevant role in processes through their interactions neuronal membranes. However, determinants cytotoxicity these still unclear. Here we used liposomes toxic nontoxic same protein to measure quantitatively affinity two oligomeric species for lipid To this aim, quantified perturbation membranes caused using fluorescence quenching probes embedded polar apolar regions well-defined protein–oligomer binding assay fluorescently labeled determine Stern–Volmer dissociation constants, respectively. With both approaches, found that have membrane 20–25 times higher than oligomers. Circular dichroism, intrinsic fluorescence, FRET indicated neither oligomer type changes its structure upon interaction. Using enriched trodusquemine, potential small molecule drug known penetrate make them refractory oligomers, was remarkably lower. At protective concentrations molecule, fully prevented. Furthermore, increase slightly decrease GM1 ganglioside cholesterol content, respectively, indicating physicochemical properties modulate species.