Microglial TDP-43 mediates myelin refinement and represses Tyrobp cryptic exon inclusion in mice
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.
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BibTeX
@article{compagnion2026microglial,
title = {{Microglial TDP-43 mediates myelin refinement and represses Tyrobp cryptic exon inclusion in mice}},
author = {Anne-Claire Compagnion and Andranik Ivanov and Anil Rana and Felipe Espinoza and Thomas Sandmann and Fanny Martineau and Katia Monsorno and Roberta Facchinetti and Alessandro Matera and Lionel Rougé and Fernando González Ibáñez and Clarissa Catale and Matteo Bizzotto and Sonia Garel and Michela Matteoli and Yutaro Kashiwagi and Ryuta Koyama and Christian Haass and Marie-Eve Tremblay and Dieter Beule and Ileana Jelescu and Valerio Zerbi and Gilbert Di Paolo and Rosa Paolicelli},
journal = {Nature Neuroscience},
year = {2026},
month = jul,
doi = {10.1038/s41593-026-02348-3},
url = {https://hal.science/hal-05756431v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Microglial TDP-43 mediates myelin refinement and represses Tyrobp cryptic exon inclusion in mice
AU - Anne-Claire Compagnion
AU - Andranik Ivanov
AU - Anil Rana
AU - Felipe Espinoza
AU - Thomas Sandmann
AU - Fanny Martineau
AU - Katia Monsorno
AU - Roberta Facchinetti
AU - Alessandro Matera
AU - Lionel Rougé
AU - Fernando González Ibáñez
AU - Clarissa Catale
AU - Matteo Bizzotto
AU - Sonia Garel
AU - Michela Matteoli
AU - Yutaro Kashiwagi
AU - Ryuta Koyama
AU - Christian Haass
AU - Marie-Eve Tremblay
AU - Dieter Beule
AU - Ileana Jelescu
AU - Valerio Zerbi
AU - Gilbert Di Paolo
AU - Rosa Paolicelli
PY - 2026
DA - 2026/07/08
JO - Nature Neuroscience
DO - 10.1038/s41593-026-02348-3
UR - https://hal.science/hal-05756431v1
AB - 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.
SN - 1097-6256
SN - 1546-1726
ER -