Unravelling the Structural Organization of Individual α-Synuclein Oligomers Grown in the Presence of Phospholipids

Parkinson's disease (PD) is a severe neurological disorder that affects more than 1 million people in the U.S. alone. A hallmark of PD is the formation of intracellular α-synuclein (α-Syn) protein aggregates called Lewy bodies (LBs). Although this protein does not have a particular localization in the central neural system, α-Syn aggregates are primarily found in certain areas of the midbrain, hypothalamus, and thalamus. Microscopic analysis of LBs reveals fragments of lipid-rich membranes, organelles, and vesicles. These and other pieces of experimental evidence suggest that α-Syn aggregation can be triggered by lipids. In this study, we used atomic force microscope infrared spectroscopy (AFM-IR) to investigate the structural organization of individual α-Syn oligomers grown in the presence of two different phospholipids vesicles. AFM-IR is a modern optical nanoscopy technique that has single-molecule sensitivity and subdiffraction spatial resolution. Our results show that α-Syn oligomers grown in the presence of phosphatidylcholine have a distinctly different structure than oligomers grown in the presence of phosphatidylserine. We infer that this occurs because of specific charges adopted by lipids, which in turn governs protein aggregation. We also found that the protein to phospholipid ratio has a substantial impact on the structure of α-Syn oligomers. These findings demonstrate that α-Syn is far more complex than expected from the perspective of the structural organization of oligomeric species.