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

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, 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. 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 novel role for TDP-43 in regulating the TREM2-DAP12 axis in mice, highlighting a previously unrecognized mechanism by which TDP-43 controls microglial function.