Elucidation of Secondary Structure and Toxicity of a-Synuclein Oligomers and Fibrils Grown in the Presence of Phosphatidylcholine and Phosphatidylserine

Abrupt aggregation of a-synuclein (a-Syn) in the midbrain hypothalamus and thalamus is a hallmark of Parkinson's disease (PD), the fastest growing neurodegenerative pathology, projected to strike 12 million people by 2040 worldwide. In this study, we examine the effect of two phospholipids that are present in neuronal membranes, phosphatidylcholine (PC) and phosphatidylserine (PS), on the rate of a-Syn aggregation. We found that PS accelerated a-Syn aggregation, whereas PC strongly inhibited a-Syn aggregation. We also utilized the nano-infrared imaging technique, also known as atomic force microscopy infrared (AFM-IR) spectroscopy, to investigate whether PC and PS only change the rates or also modify the secondary structure of a-Syn aggregates. We found that both phospholipids uniquely altered the secondary structure of a-Syn aggregates present at the lag and growth phase, as well as the late stage of protein aggregation. In addition, compared to the a-Syn aggregates formed in the lipid-free environment, a-Syn:PC and a-Syn:PS aggregates demonstrated higher cellular toxicity to N27 rat neurons. Interestingly, both a-Syn:PC and a-Syn:PS aggregates showed similar levels of oxidative stress, but a-Syn:PC aggregates exhibited a greater degree of mitochondrial dysfunction compared to a-Syn:PS aggregates.