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2 Publications visible to you, out of a total of 2
A transcriptomic microglia taxonomy across mouse and human pathologies

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Abstract Single-cell studies have revealed substantial microglial diversity in development, homeostasis and disease. However, a framework enabling comparison and stratification of microglial states … microglial states across contexts is needed. Here we generated an atlas of myeloid cell states by single-cell RNA sequencing more than one million central nervous system cells from more than 30 physiological and pathological conditions. This atlas enables us to establish a comprehensive taxonomy of myeloid cell states across brain disorders and related mouse models, comprising 27 superclusters and 192 clusters that are prevalent across diseases and largely conserved. We augment this taxonomic framework with spatial transcriptomics to map how immune cell states are organized within tissue and interact with their local cellular environment. Using in vivo perturbations, we also show that activation-associated microglial states are dependent on interferon and colony-stimulating factor 1 receptor signaling. Together, these findings provide a spatially aware taxonomic framework for central nervous system immune cells in health and disease.

Authors: Chintan Chhatbar, Roman Sankowski, Michael Schulz, Takashi Shimizu, Marius Schwabenland, Ori Staszewski, Christian Scheiwe, Stefan Nessler, Katharina Borst, Anaelle Aurelie Dumas, Ella Trost, Daniel Berchtold, Wesley Brandão, Omar Mossad, Adrià Dalmau Gasull, Maximilian Frosch, Daniel Erny, Martin Diebold, Elena Guffart, Katharina Ternka, Mihaela Guranda, Janaki Manoja Vinnakota, Marina Friesen, Koliane Ouk, Inken Waltl, Michael LaMorte, Timothy R. Hammond, Giovanni Di Liberto, Ilena Vincenti, Mario Kreutzfeldt, Ibrahim T. Mughrabi, Yousef Al-Abed, Thomas Blank, Melanie Meyer-Luehmann, Yanick J. Crow, Nellwyn Hagen, Dimitry Ofengeim, Robert Zeiser, Matthias Kettwig, Jutta Gärtner, Andreas Meisel, Martin Schwemmle, Ulrich Kalinke, Jürgen Beck, Bertram Bengsch, Robert Thimme, Oleg Butovsky, Tamara Seredenina, Richard M. Ransohoff, Francisco J. Quintana, Katrin Kierdorf, Doron Merkler, Christine Stadelmann, Josef Priller, Marco Prinz

Date Published: 25th Mar 2026

Publication Type: Journal Article

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

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Abstract As tissue-resident macrophages of the central nervous system parenchyma, microglia perform diverse essential functions during homeostasis and perturbations 1 . They primarily interact with …ions 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.

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

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