中国科学院上海有机化学研究所刘聪研究组发现，溶血磷脂酰胆碱结合α-突触核蛋白并阻止其病理聚集。2024年5月25日，国际知名学术期刊《国家科学评论》在线发表了这一成果。

研究人员表示，路易体中聚集的α-突触核蛋白（α-syn）是帕金森病（PD）的病理标志。脂质代谢的基因突变是部分帕金森病患者的致病原因。α-syn的脂质相互作用在其功能和聚集中的作用已得到公认，但具体涉及哪些脂质以及脂质代谢问题如何引发α-syn聚集和神经退行性变仍不清楚。

研究人员发现α-syn显示出与溶血磷脂（LPL）结合的偏好，尤其是以溶血磷脂酰胆碱（LPC）为靶标，而不依赖于静电相互作用。LPC能够使α-syn保持紧凑的构象，大大降低其在体外和细胞环境中的聚集倾向。相反，细胞LPL的产生减少与α-syn的聚集增加有关。该研究强调了LPL在保持α-syn的自然构象以抑制不适当聚集方面所起的关键作用，并在PD的脂质代谢功能障碍和α-syn聚集之间建立了潜在的联系。

附：英文原文

Title: Lysophosphatidylcholine binds α-synuclein and prevents its pathological aggregation

Author: Zhao, Chunyu, Tu, Jia, Wang, Chuchu, Liu, Wenbin, Gu, Jinge, Yin, Yandong, Zhang, Shengnan, Li, Dan, Diao, Jiajie, Zhu, Zheng-Jiang, Liu, Cong

Issue&Volume: 2024-05-25

Abstract: Accumulation of aggregated α-synuclein (α-syn) in Lewy bodies is the pathological hallmark of Parkinson's disease (PD). Genetic mutations in lipid metabolism are causative for a subset of patients with Parkinsonism. The role of α-syn's lipid interactions in its function and aggregation is recognized, yet the specific lipids involved and how lipid metabolism issues trigger α-syn aggregation and neurodegeneration remain unclear. Here, we found that α-syn shows a preference for binding to lysophospholipids (LPLs), particularly targeting lysophosphatidylcholine (LPC) without relying on electrostatic interactions. LPC is capable of maintaining α-syn in a compact conformation, significantly reducing its propensity to aggregate both in vitro and within cellular environments. Conversely, a reduction in the production of cellular LPLs is associated with an increase in α-syn accumulation. Our work underscores the critical role of LPLs in preserving the natural conformation of α-syn to inhibit improper aggregation, and establishes a potential connection between lipid metabolic dysfunction and α-syn aggregation in PD.

DOI: 10.1093/nsr/nwae182

Source: https://dx.doi.org/10.1093/nsr/nwae182