2. Academic Validation
  3. Microglia-neuron crosstalk through Hex-GM2-MGL2 maintains brain homeostasis

Microglia-neuron crosstalk through Hex-GM2-MGL2 maintains brain homeostasis

  • Nature. 2025 Aug 6. doi: 10.1038/s41586-025-09477-y.
Maximilian Frosch 1,  Takashi Shimizu 1,  Emile Wogram 1,  Lukas Amann 1,  Lars Gruber 2 3,  Ayelén I Groisman 4,  Maximilian Fliegauf 1 5,  Marius Schwabenland 1,  Chintan Chhatbar 1,  Sabrina Zechel 6,  Hendrik Rosewich 7 8,  Jutta Gärtner 8,  Francisco J Quintana 9 10,  Joerg M Buescher 11,  Thomas Blank 1,  Harald Binder 12 13 14,  Christine Stadelmann 6,  Johannes J Letzkus 4 15,  Carsten Hopf 2 3 16,  Takahiro Masuda # 17,  Klaus-Peter Knobeloch # 1 14,  Marco Prinz # 18 19 20
Affiliations

Affiliations

  • 1 Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 2 Center for Mass Spectrometry and Optical Spectroscopy (CeMOS), Mannheim University of Applied Sciences, Mannheim, Germany.
  • 3 Medical Faculty, Heidelberg University, Heidelberg, Germany.
  • 4 Institute for Physiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 5 Department of Pharmaceutical Biology and Biotechnology, Institute of Pharmaceutical Sciences, University of Freiburg, Freiburg, Germany.
  • 6 Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.
  • 7 Department of Child Neurology, Developmental Neurology, General Pediatrics, Diabetology, Endocrinology, Social Pediatrics, University Hospital Tübingen, Tübingen, Germany.
  • 8 Division of Pediatric Neurology, Department of Pediatrics and Adolescent Medicine, University Medical Center Göttingen, Georg August University, Göttingen, Germany.
  • 9 Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 10 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 11 Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
  • 12 Institute of Medical Biometry and Statistics (IMBI), Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.
  • 13 Freiburg Center for Data Analysis, Modeling and AI, University of Freiburg, Freiburg, Germany.
  • 14 Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.
  • 15 BrainLinks-BrainTools, Intelligent Machine-Brain Interfacing Technology (IMBIT), University of Freiburg, Freiburg, Germany.
  • 16 Mannheim Center for Translational Neuroscience (MCTN), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
  • 17 Division of Molecular Neuroimmunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
  • 18 Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany. marco.prinz@uniklinik-freiburg.de.
  • 19 Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany. marco.prinz@uniklinik-freiburg.de.
  • 20 Center for Brain Research and Advancements In Neuroimmunology (BRAIN), Faculty of Medicine, University of Freiburg, Freiburg, Germany. marco.prinz@uniklinik-freiburg.de.
  • # Contributed equally.
PMID: 40769205 DOI: 10.1038/s41586-025-09477-y
Abstract

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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