弗莱堡大学Marco Prinz小组宣布他们的研究开发出了通过Hex-GM2-MGL2的小胶质细胞-神经元串扰维持大脑稳态。2025年8月6日出版的《自然》发表了这项成果。

通过结合无偏性脂质组学和高分辨率空间脂质成像，深度单细胞转录组分析和新的细胞类型特异性突变，该课题组确定了一种以前未知的小胶质细胞与神经元相互作用的模式。在稳态过程中，小胶质细胞将溶酶体酶β-己糖氨酸酶（Hex）传递给神经元，以降解神经节苷脂GM2，这是维持细胞膜组织和功能所必需的。在患有神经退行性Sandhoff病的小鼠和患者中，编码Hex β亚基的Hexb的缺失导致GM2衍生物以特有的时空方式大量积累。

在小鼠中，神经元GM2神经节苷脂随后通过N-乙酰半乳糖胺（GalNAc）残基与小胶质细胞上的巨噬细胞半乳糖型凝集素（MGL）2受体结合，导致致死性神经变性。值得注意的是，用外周源性小胶质样细胞（MLCs）替代小胶质细胞能够打破这种退行性循环并完全恢复中枢神经系统的稳态。他们的研究结果揭示了一种以GM2神经节苷脂转换为中心的双向小胶质细胞-神经元通讯的新模式，确定了一种新的小胶质病，并为这些疾病提供了新的治疗途径。

据悉，小胶质细胞作为中枢神经系统（CNS）薄壁组织内的巨噬细胞，在稳态和扰动中发挥着多种基本功能。它们主要通过突触吞噬和快速清除凋亡细胞和无功能突触与神经元相互作用。

附：英文原文

Title: Microglia–neuron crosstalk via Hex–GM2–MGL2 maintains brain homeostasis

Author: Frosch, Maximilian, Shimizu, Takashi, Wogram, Emile, Amann, Lukas, Gruber, Lars, Groisman, Ayeln I., Fliegauf, Maximilian, Schwabenland, Marius, Chhatbar, Chintan, Zechel, Sabrina, Rosewich, Hendrik, Grtner, Jutta, Quintana, Francisco J., Buescher, Joerg M., Blank, Thomas, Binder, Harald, Stadelmann, Christine, Letzkus, Johannes J., Hopf, Carsten, Masuda, Takahiro, Knobeloch, Klaus-Peter, Prinz, Marco

Issue&Volume: 2025-08-06

Abstract: As tissue resident macrophages of the central nervous system (CNS) parenchyma, microglia perform diverse essential functions during homeostasis and perturbations1. They primarily interact with neurons via synaptic engulfment and through the rapid elimination of apoptotic cells and nonfunctional synapses2. Here, by combining unbiased lipidomics and high resolution spatial lipid imaging, deep single-cell transcriptome analysis and novel cell type-specific mutants, we identified a previously unknown mode of microglial interaction with neurons. During homeostasis, microglia deliver the lysosomal enzyme β-hexosaminidase (Hex) to neurons for the degradation of the ganglioside GM2 that is integral to maintaining cell membrane organization and function. Absence of Hexb, encoding the β subunit of Hex, in both mice and patients suffering from neurodegenerative Sandhoff disease leads to a massive accumulation of GM2 derivatives in a characteristic spatiotemporal manner3. In mice, neuronal GM2 gangliosides subsequently engage the macrophage galactose-type lectin (MGL)2 receptor on microglia via N-acetylgalactosamine (GalNAc) residues, leading to lethal neurodegeneration. Notably, replacement of microglia with peripherally derived microglia-like cells (MLCs) is able to break this degenerative cycle and fully restore CNS homeostasis. Our results reveal a novel mode of bidirectional microglia-neuron communication centred around GM2 ganglioside turnover, identify a novel microgliopathy and offer novel therapeutic avenues for these maladies.

DOI: 10.1038/s41586-025-09477-y

Source: https://www.nature.com/articles/s41586-025-09477-y