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 α-synuclein (α-syn), a small protein that is abundant at presynaptic nerve termini, where it regulates cell vesicle trafficking. Due to the direct interactions of α-syn with cell membranes, a substantial amount of work was done over the past decade to understand the role of lipids in α-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 α-syn aggregation. We found that PA LUVs with 16:0, 18:0, and 18:1 FAs drastically reduced the toxicity of α-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 α-syn aggregation and altered the morphology and secondary structure of α-syn fibrils. These results indicate that PA LUVs can be used as a potential therapeutic strategy to reduce the toxicity of α-syn fibrils formed upon PD.

中文翻译：

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磷脂酸大单层囊泡降低 α-突触核蛋白原纤维的毒性

帕金森病 (PD) 是一种严重的病理学，由黑质致密部以及大脑其他区域的多巴胺能神经元进行性变性引起。这些神经变性过程与 α-突触核蛋白 (α-syn) 的突然聚集有关，α-突触核蛋白是一种小蛋白质，在突触前神经末端含量丰富，可调节细胞囊泡运输。由于 α-syn 与细胞膜的直接相互作用，在过去十年中，人们进行了大量的工作来了解脂质在 α-syn 聚集中的作用。然而，磷脂酸（PA）是一种带有小极性头的带负电的磷脂，其作用仍不清楚。在这项研究中，我们研究了 PA 大单层囊泡 (LUV) 对 α-syn 聚集的影响。我们发现，具有 16:0、18:0 和 18:1 FA 的 PA LUV 如果与蛋白质以 1:1 摩尔比存在，则可显着降低 α-syn 原纤维的毒性。我们的结果还表明，这些载体的存在改变了 α-syn 聚集的速率，并改变了 α-syn 原纤维的形态和二级结构。这些结果表明 PA LUV 可作为一种潜在的治疗策略来降低 PD 时形成的 α-syn 原纤维的毒性。