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<p>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.</p>

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Microglial TDP-43 mediates myelin refinement and represses Tyrobp cryptic exon inclusion in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Anne-Claire Compagnion,
  • Andranik Ivanov,
  • Anil Rana,
  • Felipe Espinoza,
  • Thomas Sandmann,
  • Fanny S. Martineau,
  • Katia Monsorno,
  • Roberta Facchinetti,
  • Alessandro Matera,
  • Lionel Rougé,
  • Fernando González Ibáñez,
  • Clarissa Catale,
  • Matteo Bizzotto,
  • Sonia Garel,
  • Michela Matteoli,
  • Yutaro Kashiwagi,
  • Ryuta Koyama,
  • Christian Haass,
  • Marie-Eve Tremblay,
  • Dieter Beule,
  • Ileana Jelescu,
  • Valerio Zerbi,
  • Gilbert Di Paolo,
  • Rosa C. Paolicelli

摘要

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.