Large Unilamellar Vesicles of Phosphatidic Acid Reduce the Toxicity of -Synuclein Fibrils.
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abstract
Parkinson's disease (PD) is a severe pathology that is caused by a progressive degeneration of dopaminergic neurons in substantia nigra pars compacta as well as other areas in the brain. These neurodegeneration processes are linked to the abrupt aggregation of -synuclein (-syn), a small protein that is abundant at presynaptic nerve termini, where it regulates cell vesicle trafficking. Due to the direct interactions of -syn with cell membranes, a substantial amount of work was done over the past decade to understand the role of lipids in -syn aggregation. However, the role of phosphatidic acid (PA), a negatively charged phospholipid with a small polar head, remains unclear. In this study, we examined the effect of PA large unilamellar vesicles (LUVs) on -syn aggregation. We found that PA LUVs with 16:0, 18:0, and 18:1 FAs drastically reduced the toxicity of -syn fibrils if were present in a 1:1 molar ratio with the protein. Our results also showed that the presence of these vehicles changed the rate of -syn aggregation and altered the morphology and secondary structure of -syn fibrils. These results indicate that PA LUVs can be used as a potential therapeutic strategy to reduce the toxicity of -syn fibrils formed upon PD.
