12:15pm, 101 Bradfield Hall: TDP-43 is essential for proper microglial activities and brain homeostasis.

TDP-43 is a DNA/RNA binding protein critical for RNA metabolism. Accumulation of cytoplasmic TDP-43 inclusions accompanied by nuclear TDP-43 depletion is a molecular hallmark of TDP-43 proteinopathies in many neurodegenerative diseases. Previous studies have shown that loss of TDP-43 results in drastic alterations in neuronal RNA metabolism. However, the function of TDP-43 in microglia, the resident immune cells of the central nervous system, remains poorly understood. Here, we found that TDP-43 knockdown causes significant alterations in gene expression and RNA splicing patterns, as well as substantial reductions in microglial viability in vitro. Furthermore, microglia-specific ablation of TDP-43 in mice results in reduced microglia numbers and altered microglial activation states, which lead to subsequent changes in other brain cell types as revealed by single-nucleus RNA-seq analysis. Taken together, our data demonstrate that loss of TDP-43 function leads to severe transcriptomic changes in microglia, thereby impairing their fundamental roles in maintaining nervous system homeostasis.