The role of phospholipid saturation and composition in α‐synuclein aggregation and toxicity: A dual in vitro and in vivo approach

Parkinson's disease is characterized by a progressive accumulation of α-synuclein (α-syn) aggregates in Lewy bodies, extracellular deposits found in the midbrain, hypothalamus, and thalamus. The rate of α-syn aggregation, as well as the secondary structure of α-syn oligomers and fibrils, can be uniquely altered by lipids. However, the role of saturation of fatty acids (FAs) in such lipids in the aggregation properties of α-syn remains unclear. In this study, we investigated the effect of saturation of FAs in phosphatidylcholine (PC) and cardiolipin (CL), as well as a mixture of these phospholipids on the rate of α-syn aggregation. We found that although saturation plays very little if any role in the rate of protein aggregation and morphology of α-syn aggregates, it determined the secondary structure of α-syn oligomers and fibrils. Furthermore, we found that aggregates formed in the presence of both saturated and unsaturated PC and CL, as well as mixtures of these phospholipids, exert significantly higher cell toxicity compared to the protein aggregates formed in the lipid-free environment. To extend these findings, we conducted in vivo studies using C. elegans, where we assessed the effect of lipid-modified α-syn aggregates on organismal survival and neurotoxicity. Our results suggest that the saturation of FAs in phospholipids present in the plasma and mitochondrial membranes can be a key determinant of the secondary structure and, consequently, the toxicity of α-syn oligomers and fibrils. These findings provide new insights into the role of lipids in Parkinson's disease pathogenesis and highlight potential targets for therapeutic intervention.