Ali Abid, Holman Aidan P, Rodriguez Axell, Zhaliazka Kiryl, Osborne Luke, Kurouski Dmitry
Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, United States.
Department of Entomology, Texas A&M University, College Station, Texas 77843, United States.
Mol Pharm. 2024 Mar 4;21(3):1334-1341. doi: 10.1021/acs.molpharmaceut.3c01012. Epub 2024 Feb 19.
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.
帕金森病（PD）是一种严重的病理状况，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退化引起。这些神经退行性变过程与α-突触核蛋白（α-syn）的突然聚集有关，α-syn是一种在突触前神经末梢大量存在的小蛋白质，在那里它调节细胞囊泡运输。由于α-syn与细胞膜的直接相互作用，在过去十年中开展了大量工作来了解脂质在α-syn聚集过程中的作用。然而，磷脂酸（PA）这种具有小极性头部的带负电荷磷脂的作用仍不清楚。在本研究中，我们研究了PA大单层囊泡（LUVs）对α-syn聚集的影响。我们发现，含有16:0、18:0和18:1脂肪酸的PA LUVs如果与蛋白质以1:1的摩尔比存在，会显著降低α-syn原纤维的毒性。我们的结果还表明，这些囊泡的存在改变了α-syn的聚集速率，并改变了α-syn原纤维的形态和二级结构。这些结果表明，PA LUVs可作为一种潜在的治疗策略，以降低帕金森病中形成的α-syn原纤维的毒性。
