Changes in the concentration of phosphatidylcholine in lipid bilayers determines the aggregation rate of transthyretin

Transthyretin (TTR) is a tetrameric transporter of retinol and thyroxine that aggregates in the central and peripheral nervous system upon a severe pathology known as transthyretin amyloidosis. Although small molecular weight drugs can stabilize TTR preventing its aggregation, molecular mechanisms of transthyretin amyloidosis remain poorly understood. Accumulating evidence indicates that lipids can alter TTR stability by facilitating protein aggregation into toxic oligomers and fibrils. Consequently, pathological changes in the lipid composition of plasma membranes can be responsible for the onset and progression of transthyretin amyloidosis. In this study, we investigated the role of concentration-dependent changes in phosphatidylcholine (PC), one of the most abundant phospholipids in the plasma membrane, on the rate of TTR aggregation. For this, TTR was exposed to large unilamellar vesicles (LUVs) composed of 30%, 35%, and 40% PC. We found that a decrease in the concentration of PC from 40% to 35% drastically accelerated TTR aggregation. We also observed an increase in the cytotoxicity of TTR aggregates formed in the presence of 35% PC compared to TTR fibrils grown in the presence of LUVs with 40% PC. These results indicate that changes in the concentration of PC in the plasma membrane could trigger amyloid formation that leads to transthyretin amyloidosis. • The rate of transthyretin aggregation directly depends on the concentration of phosphatidylcholine in lipid bilayers. • With an increase in the concentration of phosphatidylcholine from 30% to 40%, the amount of unordered secondary structure in transthyretin fibrils increased from 35.5% to 71.3%. • An increase in the concentration of phosphatidylcholine from 30% to 40% lowered cytotoxicity of transthyretin fibrils increased from 23.1% to 8.2%.