Department of Pharmacology and Therapeutic Innovation, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto 390-8621, Japan.
Biomed Pharmacother. 2022 Dec;156:113891. doi: 10.1016/j.biopha.2022.113891. Epub 2022 Oct 18.
Accumulation and aggregation of α-Synuclein (α-Syn) are the hallmarks of the incidence of α-Synucleinopathies, which comprises dementia with Lewy bodies (LBs). Aggregation inhibitors are anticipated to reduce α-Syn toxicity and serve as therapeutic agents. As a result, α-Syn is regarded as the potential and priority target for drug development. Here, we report inhibition of α-Syn aggregation by a certain lysophospholipids (LPLs) species. LPLs are small bioactive lipid molecules characterized by a single carbon chain and polar head group. The LPLs used here were extracted from porcine liver decomposition product (PLDP), which was previously reported to enhance cognitive function in healthy older adults. In this study, we found that PLDP-extracted lipids (PEL) reduced α-Syn aggregation in a cellular model. In particular, lysophosphatidylcholine (LPC) 16:0, LPC18:0, LPC18:1, and lysophosphatidylethanolamine (LPE) 16:0, which are known to be contained in PEL, were found to strongly inhibit α-Syn aggregation. Furthermore, when α-Syn was co-incubated with LPLs, the fluorescence emission of Thioflavin-T (ThT) declined remarkably, indicating a lower fibril formation. Interestingly, differences were observed in the degrees of effect on the reduction of insoluble α-Syn among each LPL. In this context, LPC18:1 and LPE18:1 appeared to interact with α-Syn below 1 nM in vitro. Taken together, these studies indicated the potential of PLDP-derived LPLs as effective therapeutic agents against α-Synucleinopathies.
α-突触核蛋白（α-Syn）的聚集和聚集是α-突触核蛋白病发病的标志，其中包括路易体痴呆症（LBs）。聚集抑制剂有望降低α-Syn 的毒性并作为治疗剂。因此，α-Syn 被认为是药物开发的潜在和优先目标。在这里，我们报告了某种溶血磷脂（LPL）物种抑制α-Syn 聚集。LPL 是一种具有单碳链和极性头基团的小生物活性脂质分子。这里使用的 LPL 是从猪肝分解产物（PLDP）中提取的，先前的研究表明它可以增强健康老年人的认知功能。在这项研究中，我们发现 PLDP 提取的脂质（PEL）可减少细胞模型中的α-Syn 聚集。特别是，溶血磷脂酰胆碱（LPC）16:0、LPC18:0、LPC18:1 和溶血磷脂酰乙醇胺（LPE）16:0，已知存在于 PEL 中，被发现强烈抑制α-Syn 聚集。此外，当α-Syn 与 LPL 共孵育时，硫黄素-T（ThT）的荧光发射显着下降，表明纤维形成减少。有趣的是，在每种 LPL 对降低不溶性α-Syn 的效果程度上观察到差异。在这种情况下，LPC18:1 和 LPE18:1 似乎在体外以低于 1 nM 的浓度与α-Syn 相互作用。总之，这些研究表明 PLDP 衍生的 LPL 作为针对α-突触核蛋白病的有效治疗剂具有潜力。
