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Updated: Jul 10, 2026
Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
Microglial TDP-43 mediates myelin refinement and represses Tyrobp cryptic exon inclusion in mice
Anne-Claire Compagnion1, Andranik Ivanov2, Anil Rana3
1Department of Biomedical Sciences, University of Lausanne, Lausanne, 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.
Insights
Microglial TDP-43 loss causes myelin defects and motor deficits in mice by impairing myelin clearance and disrupting TREM2 signaling via DAP12. This reveals a novel role for TDP-43 in microglial function.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- TDP-43 proteinopathy is linked to neurodegenerative diseases like ALS and FTD.
- Mislocalization of TDP-43 is observed in neurons and glial cells.
- The specific role of TDP-43 in microglia remains largely unknown.
Purpose of the Study:
- To investigate the function of TDP-43 in microglia.
- To explore the consequences of microglial TDP-43 loss of function.
- To elucidate the molecular mechanisms underlying TDP-43's role in microglial health.
Main Methods:
- Magnetic resonance imaging (MRI) and advanced microscopy (confocal, electron).
- Spatial transcriptomics for gene expression analysis.
- Genetic manipulation (TDP-43 knockout in microglia).
Main Results:
- Microglial TDP-43 deficiency caused structural brain changes and myelin abnormalities.
- Spatial transcriptomics identified an interferon-responsive signature linked to oligodendrocyte dysfunction.
- Loss of microglial TDP-43 impaired myelin engulfment and degradation, leading to motor deficits.
Conclusions:
- TDP-43 is crucial for maintaining microglial phagocytic function, particularly myelin clearance.
- Microglial TDP-43 regulates the TREM2-DAP12 signaling pathway.
- Dysfunctional microglial TDP-43 contributes to neuroinflammation and motor deficits, offering new therapeutic targets.
