近日，厦门大学王鑫及其课题组发现，β2-微球蛋白作为内源性NMDAR拮抗剂发挥着损害突触功能的作用。2023年3月2日出版的《细胞》杂志发表了这项成果。
通过使用旁观者和血浆输注，研究人员发现血源性因素驱动唐氏综合症（DS）的突触缺陷。蛋白质组分析显示，人类DS血浆中的β2-微球蛋白（B2M）升高，这是一种主要的组织相容性复合体I类（MHC-I）成分。在野生型小鼠中全身注射B2M导致了与DS小鼠类似的突触和记忆缺陷。此外，B2m的遗传去除或全身给予抗B2m抗体可抵消DS小鼠的突触缺陷。从机制上讲，研究人员证明B2M通过与GluN1-S2环的相互作用来拮抗NMDA受体（NMDAR）的功能；用竞争性肽阻断B2M-NMDAR的相互作用，可恢复NMDAR依赖的突触功能。这些研究结果确定了B2M是一种内源性NMDAR拮抗剂，并揭示了循环的B2M在DS和相关认知障碍的NMDAR功能障碍中的病理生理作用。
据悉，DS是一种具有多种免疫相关症状的神经系统疾病；然而，中枢神经系统和外周免疫系统之间的交流仍未被探明。
附：英文原文
Title: β2-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function
Author: Yue Gao, Yujuan Hong, Lihong Huang, Shuang Zheng, Haibin Zhang, Shihua Wang, Yi Yao, Yini Zhao, Lin Zhu, Qiang Xu, Xuhui Chai, Yuanyuan Zeng, Yuzhe Zeng, Liangkai Zheng, Yulin Zhou, Hong Luo, Xian Zhang, Hongfeng Zhang, Ying Zhou, Guo Fu, Hao Sun, Timothy Y. Huang, Qiuyang Zheng, Huaxi Xu, Xin Wang
Issue&Volume: 2023/03/02
Abstract: Down syndrome (DS) is a neurological disorder with multiple immune-related symptoms;however, crosstalk between the CNS and peripheral immune system remains unexplored.Using parabiosis and plasma infusion, we found that blood-borne factors drive synapticdeficits in DS. Proteomic analysis revealed elevation of β2-microglobulin (B2M), amajor histocompatibility complex class I (MHC-I) component, in human DS plasma. Systemicadministration of B2M in wild-type mice led to synaptic and memory defects similarto those observed in DS mice. Moreover, genetic ablation of B2m or systemic administration of an anti-B2M antibody counteracts synaptic impairmentsin DS mice. Mechanistically, we demonstrate that B2M antagonizes NMDA receptor (NMDAR)function through interactions with the GluN1-S2 loop; blocking B2M-NMDAR interactionsusing competitive peptides restores NMDAR-dependent synaptic function. Our findingsidentify B2M as an endogenous NMDAR antagonist and reveal a pathophysiological rolefor circulating B2M in NMDAR dysfunction in DS and related cognitive disorders.
DOI: 10.1016/j.cell.2023.01.021
Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00051-X