Microglial TDP-43 mediates myelin refinement and represses Tyrobp cryptic exon inclusion in mice.
Overview
18 affiliations
- Department of Biomedical Sciences, University of Lausanne,Lausanne, Switzerland
- Core Unit Bioinformatics, Berlin Institute of Health, Charité—Universitätsmedizin Berlin,Berlin, Germany
- Denali Therapeutics,South San Francisco, CA USA
- Department of Life Sciences, Health and Health Professions, Link Campus University,Rome, Italy
- Département de Médecine Moléculaire, Faculté de Médecine, Université Laval,Quebec City, Quebec Canada
- School of Medical Sciences, University of Victoria,Victoria, British Columbia Canada
- Institut de Biologie de l’Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, Université PSL, Team Brain Development and Plasticity,Paris, France
- Collège de France, Université PSL,Paris, France
- IRCCS Humanitas Research Hospital,Rozzano, Italy
- Humanitas University,Pieve Emanuele, Italy
- Department of Cellular Neurobiology, Graduate School of Medicine, The University of Tokyo,Tokyo, Japan
- Department of Translational Neurobiology, National Institute of Neuroscience, National Center of Neurology and Psychiatry,Tokyo, Japan
- Biomedical Center (BMC), Department of Anatomy and Cell Biology, Faculty of Medicine, Ludwig-Maximilians-Universität München,Planegg-Martinsried, Germany
- Munich Cluster of Systems Neurology (SyNergy),Munich, Germany
- German Center for Neurodegenerative Diseases (DZNE),Munich, Germany
- Department of Radiology, Lausanne University Hospital,Lausanne, Switzerland
- Department of Psychiatry, Faculty of Medicine, University of Geneva,Geneva, Switzerland
- Department of Basic Neurosciences, Faculty of Medicine, University of Geneva,Geneva, Switzerland
Abstract
TDP-43 proteinopathy is a hallmark of neurodegenerative disorders such as amyotrophic lateral sclerosis and frontotemporal dementia where mislocalization of TDP-43 has been observed in neurons and glial cells. However, the role of TDP-43 in microglia and the consequences of its loss of function remain unexplored. Combining magnetic resonance imaging, and confocal, and electron microscopy, we uncovered structural changes and myelin abnormalities in the early postnatal brain of mice lacking microglial TDP-43. Spatial transcriptomics further revealed an enriched interferon-responsive signature associated with oligodendrocyte dysfunction. Early depletion of microglial TDP-43 led to motor deficits in adult mice. Mechanistically, knocking out TDP-43 impaired microglial ability to engulf and degrade myelin. It also led to cryptic exon inclusion in the Tyrobp mRNA, resulting in truncated DAP12 protein, thus causing defective TREM2 signaling. Our findings reveal a role for TDP-43 in regulating the TREM2-DAP12 axis in mice, highlighting a previously unrecognized mechanism through which TDP-43 controls microglial function.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
The paper links to its data, not to its authors' code: see the Data section.
Code availability
No custom software codes were used in the data analysis for this paper.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- geo:GSE309857, at NCBI GEO; found in “Data availability”
Data availability
10x Visium spatial transcriptomics dataset is publicly available on GEO repository under accession GSE309857 (https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 2, 28 September 2026
- Publisher: n/a → Nature Portfolio
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 24 authors, 2 keywords, 13 MeSH terms, 7 funders, 72 references, 2 RRIDs.
Cite
This paper
Compagnion, A.-C., Ivanov, A., Rana, A., Espinoza, F., Sandmann, T., Martineau, F. S., Monsorno, K., Facchinetti, R., Matera, A., Rougé, L., González Ibáñez, F., Catale, C., Bizzotto, M., Garel, S., Matteoli, M., Kashiwagi, Y., Koyama, R., Haass, C., Tremblay, M.-E., . . . Paolicelli, R. C. (2026). Microglial TDP-43 mediates myelin refinement and represses Tyrobp cryptic exon inclusion in mice. Nature neuroscience, 29(8), 1841-1857. https://
BibTeX
@article{compagnion2026m
author = {Compagnion, Anne-Claire and Ivanov, Andranik and Rana, Anil and Espinoza, Felipe and Sandmann, Thomas and Martineau, Fanny S. and Monsorno, Katia and Facchinetti, Roberta and Matera, Alessandro and Rougé, Lionel and González Ibáñez, Fernando and Catale, Clarissa and Bizzotto, Matteo and Garel, Sonia and Matteoli, Michela and Kashiwagi, Yutaro and Koyama, Ryuta and Haass, Christian and Tremblay, Marie-Eve and Beule, Dieter and Jelescu, Ileana and Zerbi, Valerio and Di Paolo, Gilbert and Paolicelli, Rosa C.},
title = {{Microglial TDP-43 mediates myelin refinement and represses Tyrobp cryptic exon inclusion in mice}},
journal = {Nature neuroscience},
year = {2026},
month = jul,
volume = {29},
number = {8},
pages = {1841--1857},
publisher = {Nature Portfolio},
issn = {1097-6256},
doi = {10.1038/
url = {https://
pmid = {42420559},
pmcid = {PMC13433257}
}
RIS
TY - JOUR
AU - Compagnion, Anne-Claire
AU - Ivanov, Andranik
AU - Rana, Anil
AU - Espinoza, Felipe
AU - Sandmann, Thomas
AU - Martineau, Fanny S.
AU - Monsorno, Katia
AU - Facchinetti, Roberta
AU - Matera, Alessandro
AU - Rougé, Lionel
AU - González Ibáñez, Fernando
AU - Catale, Clarissa
AU - Bizzotto, Matteo
AU - Garel, Sonia
AU - Matteoli, Michela
AU - Kashiwagi, Yutaro
AU - Koyama, Ryuta
AU - Haass, Christian
AU - Tremblay, Marie-Eve
AU - Beule, Dieter
AU - Jelescu, Ileana
AU - Zerbi, Valerio
AU - Di Paolo, Gilbert
AU - Paolicelli, Rosa C.
TI - Microglial TDP-43 mediates myelin refinement and represses Tyrobp cryptic exon inclusion in mice
T2 - Nature neuroscience
J2 - Nat Neurosci
PY - 2026
DA - 2026/
VL - 29
IS - 8
SP - 1841
EP - 1857
SN - 1097-6256
PB - Nature Portfolio
DO - 10.1038/
UR - https://
LA - en
ER -
CSL-JSON
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