It has been hypothesized that --Parkinson's disease (PD) may be initiated in the gastrointestinal tract, before manifesting in the central nervous system. In this respect, it was demonstrated that lipopolysaccharide (LPS), an endotoxin from gram-negative bacteria, accelerates the in vitro formation of α-synuclein (aSyn) fibrils, whose intracellular deposits is a histological hallmark of the degeneration of dopaminergic neurons in PD. Herein, N-terminal acetylation and missense mutations of aSyn (A30P, A53T, E46K, H50Q and G51D) linked to rare, early-onset forms of familial PD were investigated regarding their effect on aSyn aggregation stimulated by either LPS or small unilamellar lipid vesicles (SUVs). Our findings indicated that LPS as well as SUVs induce the fibrillation of N-terminally acetylated wild-type aSyn (Ac-aSyn-WT) more remarkably than the non-acetylated protein, while the LPS-free protein alone did not undergo fibrillation under our assay conditions. In addition, with the exception of A30P, PD mutations increased the fibrillation of Ac-aSyn in the presence of LPS compared with Ac-aSyn-WT. The most pronounced effect of LPS was noticed for A53T, as observed when either Thioflavin-T or JC-1 were used as fluorescent probes for fibrils. Overall, our results suggest for the first time the existence of a synergy between LPS and PD mutations/N-terminal acetylation toward aSyn fibrillation.

中文翻译：

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细菌内毒素和脂囊泡引发的 α-突触核蛋白纤维颤动受 N 端乙酰化和家族性帕金森病突变的调节

据推测，帕金森病 (PD) 可能始于胃肠道，然后出现在中枢神经系统中。在这方面，研究表明脂多糖（LPS）是一种来自革兰氏阴性细菌的内毒素，可加速α-突触核蛋白（aSyn）原纤维的体外形成，其细胞内沉积物是 PD 中多巴胺能神经元变性的组织学标志。在此，研究了与罕见的早发性家族性 PD 相关的 aSyn N 端乙酰化和错义突变（A30P、A53T、E46K、H50Q 和 G51D），了解它们对 LPS 或小单层脂质囊泡刺激的 aSyn 聚集的影响（SUV）。我们的研究结果表明，LPS 以及 SUV 比非乙酰化蛋白更显着地诱导 N 末端乙酰化野生型 aSyn (Ac-aSyn-WT) 发生原纤维化，而单独不含 LPS 的蛋白质在我们的研究下并未发生原纤维化。测定条件。此外，与 Ac-aSyn-WT 相比，除 A30P 外，PD 突变在 LPS 存在下增加了 Ac-aSyn 的颤动。当硫磺素-T 或 JC-1 用作原纤维荧光探针时观察到，LPS 对 A53T 的影响最为显着。总体而言，我们的结果首次表明 LPS 和 PD 突变/N 端乙酰化之间存在对 aSyn 纤维颤动的协同作用。