Microglia-neuron crosstalk via Hex-GM2-MGL2 maintains brain homeostasis.

As tissue resident macrophages of the central nervous system (CNS) parenchyma, microglia perform diverse essential functions during homeostasis and perturbations. They primarily interact with neurons via synaptic engulfment and through the rapid elimination of apoptotic cells and nonfunctional synapses. 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 manner. 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.