Adsorption of α-Synuclein on Lipid Bilayers: Modulating the Structure and Stability ofProtein Assemblies

The interaction of alpha-synuclein with phospholipid membranes has been examined using supported lipid bilayers and epi-flourescence microscopy. The membranes contained phosphatidylcholine (PC) and phosphatidic acid (PA), which mix at physiological pH. Upon protein adsorption, the lipids undergo fluid-fluid phase separation into PC-rich and PA-rich regions. The protein preferentially adsorbs to the PA-rich regions. The adsorption and subsequent aggregation of alpha-synuclein was probed by tuning several parameters: the charge oil the lipids, the charge oil the protein, and the screening environment. Conditions which promoted the greatest extent of 0 adsorption resulted ill structurally heterogenous agoregates, while comparatively homogeneous aggregates were observed under conditions whereby adsorption did not Occur as readily. Our observation that different agregation and different aggregate Structures poses a alterations to the system lead to different degrees of a challenge for drug discovery. Namely, therapies aimed tit neutralizing alpha-synuclein must target a broad range of potentially toxic, membrane-bound assemblies.