Lipids and Small Molecules Affect α-synuclein Association and Disruption of Nanodiscs

Lipid membranes have recently been implicated in protein misfolding and disease etiology, including for α-synuclein and Parkinson’s Disease. However, it is challenging to study the intersection of protein complex formation, membrane interactions, and bilayer disruption simultaneously. 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 α-synuclein-membrane interactions. α-synuclein did not interact with zwitterionic DMPC lipids but interacted strongly with anionic DMPG lipids, eventually leading to membrane disruption. Unsaturated POPG lipid nanodiscs were also prone to bilayer disruption, releasing α-synuclein:POPG complexes. Interestingly, the fibril inhibitor, (-)-epigallocatechin gallate (EGCG), prevented membrane disruption but did not prevent the incorporation of α-synuclein into nanodisc complexes. Thus, although EGCG inhibits fibrilization, it does not inhibit α-synuclein from associating with the membrane.