Microglia–neuron crosstalk through Hex–GM2–MGL2 maintains brain homeostasis
- Maximilian Frosch
- Takashi Shimizu
- Emile Wogram
- Lukas Amann
- Lars Gruber
- Ayelén I. Groisman
- Maximilian Fliegauf
- Marius Schwabenland
- Chintan Chhatbar
- Sabrina Zechel
- Hendrik Rosewich
- Jutta Gärtner
- Francisco J. Quintana
- Joerg M. Buescher
- Thomas Blank
- Harald Binder
- Christine Stadelmann
- Johannes J. Letzkus
- Carsten Hopf
- Takahiro Masuda
- Klaus-Peter Knobeloch
- Marco Prinz
2025-08-06
As tissue-resident macrophages of the central nervous system parenchyma, microglia perform diverse essential functions during homeostasis and perturbations 1 . They primarily interact with neurons by means of synaptic engulfment and through the rapid elimination of apoptotic cells and non-functional synapses 2 . 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 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 β-hexosaminidase, in both mice and patients with neurodegenerative Sandhoff disease leads to a massive accumulation of GM2 derivatives in a characteristic spatiotemporal manner 3 . In mice, neuronal GM2 gangliosides subsequently engage the macrophage galactose-type lectin 2 receptor on microglia through N -acetylgalactosamine residues, leading to lethal neurodegeneration. Notably, replacement of microglia with peripherally derived microglia-like cells is able to break this degenerative cycle and fully restore central nervous system homeostasis. Our results reveal a mode of bidirectional microglia–neuron communication centred around GM2 ganglioside turnover, identify a microgliopathy and offer therapeutic avenues for these maladies.