Phosphatidylcholine and Phosphatidylserine Uniquely Modify the Secondary Structure of α-Synuclein Oligomers Formed in Their Presence at the Early Stages of Protein Aggregation

Abrupt aggregation of alpha-synuclein (alpha-Syn) leads to a formation of highly toxic protein oligomers. These aggregates are the underlying molecular cause of an onset of the irreversible degeneration of dopaminergic neurons in midbrain, hypothalamus, and thalamus, a pathology known as Parkinson's disease. The transient nature of oligomers, as well as their structural and morphological heterogeneity, limits the use of cryo-electron microscopy and solid-state NMR, classical tools of structural biology, for elucidation of their secondary structure. Despite this limitation, numerous pieces of experimental evidence suggest that phospholipids can uniquely alter the structure and toxicity of oligomers. In this study, we utilize an innovative nano-infrared imaging technique, also known as atomic force microscopy infrared (AFM-IR) spectroscopy, to examine the structure of individual alpha-Syn oligomers grown in the presence of phosphatidylcholine (alpha-Syn:PC) and phosphatidylserine (alpha-Syn:PS). We determined the amount of the parallel and the antiparallel beta-sheets, as well as the amount the alpha- helix and the unordered protein, in the secondary structure of alpha-Syn:PC and alpha-Syn:PS formed at day 2 (D2), 8 (D8), and 15 (D15) after initiation of protein aggregation. We found a gradual decrease in the amount of the parallel beta-sheet in both alpha-Syn:PC and alpha- Syn:PS from D2 to D15 together with an increase in the alpha-helix and the unordered protein secondary structure. We infer that this is due to the presence of lipids in the structure of oligomers that prevent an expansion of the parallel beta-sheet upon interaction of the oligomers with monomeric alpha-Syn.

Automated summary

This study utilized nano-infrared imaging technique to investigate the effect of phosphatidylcholine and phosphatidylserine on the structure of alpha-synuclein oligomers. It was found that lipids can alter the secondary structure of the oligomers.