Lipids and EGCG Affect α-Synuclein Association and Disruption of Nanodiscs

Lipid membranes have recently been implicated in protein misfolding and disease etiology, including for alpha-synuclein and Parkinson's disease. However, studying the intersection of protein complex formation, membrane interactions, and bilayer disruption simultaneously is challenging. In particular, the efficacies of small molecule inhibitors for toxic protein aggregation are not well understood. Here, we used native mass spectrometry in combination with lipid nanodiscs to study alpha-synuclein-membrane interactions. alpha-Synuclein did not interact with zwitterionic 1,2dimyristoyl-sn-glycero-3-phosphocholine lipids but interacted strongly with anionic 1,2-dimyristoyl-sn-glycero-3-phospho(1 '-racglycerol) lipids, eventually leading to membrane disruption. Unsaturated 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho ( 1 '-racglycerol) (POPG) lipid nanodiscs were also prone to bilayer disruption, releasing alpha-synuclein:POPG complexes. Interestingly, the fibril inhibitor, (-)-epigallocatechin gallate (EGCG), prevented membrane disruption but did not prevent the incorporation of alpha-synuclein into nanodisc complexes. Thus, although EGCG inhibits fibrillization, it does not inhibit alpha-synuclein from associating with the membrane.

Automated summary

Lipid membranes play a crucial role in protein misfolding and disease etiology. This study used native mass spectrometry and lipid nanodiscs to investigate the interaction between alpha-synuclein and lipid membranes. The findings suggest that specific lipids can lead to membrane disruption when interacting with alpha-synuclein, but a fibril inhibitor can prevent membrane disruption without inhibiting the binding of the protein to the membrane.