Publications

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3 Publications visible to you, out of a total of 3
Single-cell spatial transcriptomic profiling defines a pathogenic inflammatory niche in chronic active multiple sclerosis lesions

Abstract

Not specified

Authors: Ruoqing Feng, Lena Spieth, Lu Liu, Stefan Berghoff, Jonas Franz, Qian Liu, Zhen Wang, Vini Tiwari, Simona Vitale, Simon Frerich, Sergi Florensa, Niklas Junker, Ludwig Huber, Marco Keller, Christoph Müller, Franz Bracher, Xiaoke Ge, Patrick C.N. Rensen, Gijs Kooij, Leon Hosang, Serhii Chornyi, Martin Dichgans, Ozgun Gokce, Gesine Saher, Christine Stadelmann, Martin Giera, Janos Groh, Mikael Simons

Date Published: 1st Dec 2025

Publication Type: Journal Article

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

Abstract (Expand)

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

Pro-inflammatory activation following demyelination is required for myelin clearance and oligodendrogenesis

Abstract (Expand)

Remyelination requires innate immune system function, but how exactly microglia and macrophages clear myelin debris after injury and tailor a specific regenerative response is unclear. Here, we asked … whether pro-inflammatory microglial/macrophage activation is required for this process. We established a novel toxin-based spinal cord model of de- and remyelination in zebrafish and showed that pro-inflammatory NF-κB–dependent activation in phagocytes occurs rapidly after myelin injury. We found that the pro-inflammatory response depends on myeloid differentiation primary response 88 (MyD88). MyD88-deficient mice and zebrafish were not only impaired in the degradation of myelin debris, but also in initiating the generation of new oligodendrocytes for myelin repair. We identified reduced generation of TNF-α in lesions of MyD88-deficient animals, a pro-inflammatory molecule that was able to induce the generation of new premyelinating oligodendrocytes. Our study shows that pro-inflammatory phagocytic signaling is required for myelin debris degradation, for inflammation resolution, and for initiating the generation of new oligodendrocytes.

Authors: Maria Inês Cunha, Minhui Su, Ludovico Cantuti-Castelvetri, Stephan A. Müller, Martina Schifferer, Minou Djannatian, Ioannis Alexopoulos, Franziska van der Meer, Anne Winkler, Tjakko J. van Ham, Bettina Schmid, Stefan F. Lichtenthaler, Christine Stadelmann, Mikael Simons

Date Published: 20th Feb 2020

Publication Type: Journal Article

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