Elucidation of Secondary Structure and Toxicity of α-Synuclein Oligomers and Fibrils Grown in the Presence of Phosphatidylcholine and Phosphatidylserine.
Elucidation of Secondary Structure and Toxicity of α-Synuclein Oligomers and Fibrils Grown in the Presence of Phosphatidylcholine and Phosphatidylserine.
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阐明在磷脂酰胆碱和磷脂酰丝氨酸存在下生长的α-突触核蛋白寡聚物和原纤维的二级结构和毒性。
DOI：
10.1021/acschemneuro.3c00314
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发表时间：
2023
影响因子：
5
通讯作者：
Kurouski,Dmitry
中科院分区：
文献类型：
--
作者：
Dou,Tianyi;Matveyenka,Mikhail;Kurouski,Dmitry
α-突触核蛋白（α-Syn）在中脑下丘脑和丘脑中的突然聚集是帕金森病（PD）的标志，帕金森病是增长最快的神经退行性疾病，预计到2040年全球将有1200万人发病。在这项研究中，我们研究了存在于神经元膜中的两种磷脂，磷脂酰胆碱（PC）和磷脂酰丝氨酸（PS）对α-Syn聚集速率的影响。我们发现PS促进α-Syn的聚集，而PC强烈抑制α-Syn的聚集。我们还利用纳米红外成像技术，也称为原子力显微镜红外（AFM-IR）光谱，研究PC和PS是否仅改变α-Syn聚集体的速率或也改变其二级结构。我们发现，这两种磷脂独特地改变了存在于滞后期和生长期以及蛋白质聚集后期的α-Syn聚集体的二级结构。此外，与在无脂质环境中形成的α-Syn聚集体相比，α-Syn：PC和α-Syn：PS聚集体对N27大鼠神经元表现出更高的细胞毒性。有趣的是，α-Syn：PC和α-Syn：PS聚集体均显示出相似的氧化应激水平，但与α-Syn：PS聚集体相比，α-Syn：PC聚集体表现出更大程度的线粒体功能障碍。
Abrupt aggregation of α-synuclein (α-Syn) in the midbrain hypothalamus and thalamus is a hallmark of Parkinson’s disease (PD), the fastest growing neurodegenerative pathology, projected to strike 12 million people by 2040 worldwide. In this study, we examine the effect of two phospholipids that are present in neuronal membranes, phosphatidylcholine (PC) and phosphatidylserine (PS), on the rate of α-Syn aggregation. We found that PS accelerated α-Syn aggregation, whereas PC strongly inhibited α-Syn aggregation. We also utilized the nano-infrared imaging technique, also known as atomic force microscopy infrared (AFM-IR) spectroscopy, to investigate whether PC and PS only change the rates or also modify the secondary structure of α-Syn aggregates. We found that both phospholipids uniquely altered the secondary structure of α-Syn aggregates present at the lag and growth phase, as well as the late stage of protein aggregation. In addition, compared to the α-Syn aggregates formed in the lipid-free environment, α-Syn:PC and α-Syn:PS aggregates demonstrated higher cellular toxicity to N27 rat neurons. Interestingly, both α-Syn:PC and α-Syn:PS aggregates showed similar levels of oxidative stress, but α-Syn:PC aggregates exhibited a greater degree of mitochondrial dysfunction compared to α-Syn:PS aggregates.