DISSECTING THE ROLE OF MICROGLIAL TDP-43 IN DEMYELINATION AND LIPID HANDLING

TDP-43 is a ubiquitously expressed DNA-RNA binding protein encoded by the TARDBP gene. Cytoplasmic TDP-43 aggregates are hallmarks of amyotrophic lateral sclerosis and a subset of frontotemporal lobar degeneration. They are also found in Alzheimer’s disease cases, mainly associated with the APOE4 risk allele, suggesting a link between TDP-43 and lipid metabolism. Microglia, the innate immune cells of the central nervous system, are key players in brain homeostasis and increasingly implicated in neurodegenerative diseases. While TDP-43 dysfunction has been ascribed primarily to neurons, accumulating evidence indicates a role in glial cells, including microglia. However, the role of TDP-43 in regulating microglial function, and in particular, its role in controlling lipid metabolism remain poorly explored. Using a microglial conditional knockout (cKO) mouse model, we show that microglia lacking TDP-43 exhibit lipid-handling deficits. RNA-sequencing of acutely sorted microglia further revealed alterations in lipid-related genes, including Ldlr and Acat1, suggesting potential impairment in microglial lipid metabolism. This prompted us to investigate whether TDP-43 would modulate microglial response following demyelination.
We used stereotaxic injection of lysophosphatidylcholine into the corpus callosum of control and TDP-43 cKO adult mice to induce focal demyelination. 14 days post-injection, cKO mice exhibited increased lesion size compared with control littermates, associated with abnormal accumulation of CD68-positive phagolysosomes. Additionally, loss of microglial TDP-43 led to a significant increase in lipid droplets in the demyelinated area. These results so far suggest that microglia lacking TDP-43 are defective in scavenging and handling myelin debris following demyelination, thus impairing the remyelination process.