The toxicities of A30P and A53T α-synuclein fibrils can be uniquely altered by the length and saturation of fatty acids in phosphatidylserine

Progressive degeneration of dopaminergic neurons in the midbrain, hypothalamus, and thalamus is a hallmark of Parkinson's disease (PD). Neuronal death is linked to the abrupt aggregation of alpha-synuclein (alpha-syn), a small protein that regulates vesicle trafficking in synaptic clefts. Studies of families with a history of PD revealed several mutations in alpha-syn including A30P and A53T that are linked to the early onset of this pathology. Numerous pieces of evidence indicate that lipids can alter the rate of protein aggregation, as well as modify the secondary structure and toxicity of amyloid oligomers and fibrils. However, the role of lipids in the stability of alpha-syn mutants remains unclear. In this study, we investigate the effect of phosphatidylserine (PS), an anionic lipid that plays an important role in the recognition of apoptotic cells by macrophages, in the stability of WT, A30P, and A53T alpha-syn. We found PS with different lengths and saturation of fatty acids accelerated the rate of WT and A30P aggregation. At the same time, the opposite effect was observed for most PS on A53T. We also found that PS with different lengths and saturation of fatty acids change the secondary structure and toxicities of WT, A30P, and A53T fibrils. These results indicate that lipids can play an important role in the onset and spread of familial PD.