Microglia–neuron crosstalk through Hex–GM2–MGL2 maintains brain homeostasis
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As tissue-resident macrophages of the central nervous system parenchyma, microglia perform diverse essential functions during homeostasis and perturbations1. They primarily interact with neurons by means of synaptic engulfment and through the rapid elimination of apoptotic cells and non-functional 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 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 manner3. 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.
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Created: 7th Aug 2026 at 10:28
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https://orcid.org/0000-0003-4108-7109
Projects: TRR 274: Checkpoints of Central Nervous System Recovery
Institutions: Universitätsmedizin Göttingen
Projects: CRC1002: Modulatory Units in Heart Failure, TRR 274: Checkpoints of Central Nervous System Recovery, SFB 1190: Compartmental Gates and Contact Sites in Cells
Web page: Not specified
https://rdp.sfb274.de/ (Research Data Platform) https://gepris.dfg.de/gepris/projekt/408885537 (DFG Gepris entry) The central nervous system (CNS) is a terminally differentiated tissue, where any insult carries a heightened risk - yet the tissue response to these insults is variable and can range from irreversible destruction to almost complete recovery. The rules that instruct these divergent outcomes are still unknown. The aim of this CRC is therefore to understand the biology of the multicellular ...
Programme: Sonderforschungsbereiche/Collaborative Research Centers
Public web page: https://www.sfb274.de/
The cerebral cortex contains a special, perineuronally localized population of oligodendrocyte lineage cells with possible functions in connectivity and myelination. We hypothesize that this cell population serves as a reservoir of remyelinating cells after myelin damage. We will apply spatial transcriptome analysis with subcellular resolution in experimental models of demyelination and human tissue from patients with multiple sclerosis to define physiological and pathological states of perineuronal ...
Submitter: Camilla Giudici
Studies: Microglia–neuron crosstalk through Hex–GM2–MGL2 maintains brain homeostasis, Pro-inflammatory activation following demyelination is required for myel..., Single-cell spatial transcriptomic profiling defines a pathogenic inflam...
Assays: Expression profiling: Bulk RNA-seq (mouse), Expression profiling: MERFISH Spatial Transcriptomics (human), Expression profiling: MERFISH Spatial Transcriptomics (mouse), Expression profiling: scRNA-seq (human), Expression profiling: scRNA-seq (human), Expression profiling: scRNA-seq (mouse), Expression profiling: snRNA-seq (mouse), Shotgun proteomics (mouse)
Submitter: Camilla Giudici
Assay type: Transcriptomics
Technology type: Sequencing
Investigation: B01 - Function of satellite oligodendrocytes in...
Submitter: Camilla Giudici
Assay type: Transcriptomics
Technology type: Sequencing
Investigation: B01 - Function of satellite oligodendrocytes in...
Submitter: Camilla Giudici
Assay type: Transcriptomics
Technology type: Sequencing
Investigation: B01 - Function of satellite oligodendrocytes in...
CNS nuclei were isolated from frozen thalamic specimen, stained with anti-NeuN and anti-Olig2, FACS purified (DAPI+NeuN-Olig2-), and analyzed with snRNA-seq
Creators: None
Submitter: Camilla Giudici
Brains were homogenized, stained, microglia were FACS-purified, RNA was isolated, cDNA was produced and sequencing libraries were prepared.
Creators: None
Submitter: Camilla Giudici
CNS nuclei were isolated from frozen thalamic specimen, FACS purified, and analyzed with snRNA-seq
Creators: None
Submitter: Camilla Giudici
CNS nuclei were isolated from frozen thalamic specimen, FACS purified, and analyzed with snRNA-seq
Creators: None
Submitter: Camilla Giudici
CNS nuclei were isolated from frozen CNS tissue specimen, stained with anti-NeuN and anti-Olig2, FACS purified (DAPI+NeuN-Olig2-), and analyzed with snRNA-seq
Creators: None
Submitter: Camilla Giudici
Abstract (Expand)
Authors: 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
Date Published: 6th Aug 2025
Publication Type: Journal Article
