MICROGLIAL TDP-43 MEDIATES MYELIN REFINEMENT DURING EARLY BRAIN DEVELOPMENT

TDP-43, encoded by the TARDBP gene, is a highly conserved DNA/RNA-binding protein that shuttles between the nucleus and cytoplasm. Aberrant cytoplasmic aggregation of TDP-43, often accompanied by its nuclear depletion, is a well-established hallmark of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). Microglia, the brain’s resident immune cells, are essential for various physiological processes critical to brain development and function. While TDP-43 mislocalization has been observed in both neurons and glial cells, its specific role in microglia, and the impact of its loss in this cell type, remains poorly understood. Recent studies have shown that TDP-43 regulates phagocytosis, and that mice conditionally lacking TDP-43 in microglia (cKO) during adulthood exhibit pathological synapse loss. Here, we hypothesize that microglial TDP-43 may also play a critical role during early brain maturation. 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.