Microglial TDP-43 mediates myelin refinement and represses Tyrobp cryptic exon inclusion in mice [RNA-seq]

However, the role of TDP-43 in microglia and the consequences of its loss-of-function remain unexplored. Combining magnetic resonance imaging, 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-response signature associated with oligodendrocyte dysfunction. Early microglial TDP-43 depletion resulted in motor deficits in adult mice. Mechanistically, knocking out TDP-43 impaired microglial ability to engulf and degrade myelin.