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

18 March 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


Native Mass Spectrometry
Protein-Lipid Interactions
Fibril Inhibitors

Supplementary materials

Supporting Information
Supporting Figures and Tables


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.