Loss of Nuclear TDP-43 Impairs Lipid Metabolism in Microglia-Like Cells

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive motor neuron loss, with TDP-43 pathology present in over 90% of cases. While neuroinflammation is a recognized hallmark, the role of microglia in ALS pathogenesis remains incompletely understood. Here, we demonstrate that TDP-43 regulates microglial function via triglyceride metabolism. Using shRNA-mediated TARDBP knockdown in human monocyte-derived microglia-like cells (MDMi), we observed suppressed cholesterol biosynthesis, upregulation of fatty acid metabolism genes, lipid droplet accumulation, enhanced phagocytic activity, and increased IL-1{beta} production. Inhibiting diacylglycerol acyltransferase (DGAT) enzymes reduced lipid droplet formation, phagocytosis, and IL-1{beta}, directly linking the triglyceride pathway to microglial activation. Patient-derived MDMi from both sporadic and TARDBP-mutant ALS cases showed overlapping as well as distinct alterations, some of which were reversed by DGAT inhibition. Our findings identify dysregulated triglyceride metabolism as a novel pathway through which TDP-43 mediates microglial dysfunction, highlighting a potential therapeutic target for ALS. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/676815v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@f10b2dorg.highwire.dtl.DTLVardef@114d48forg.highwire.dtl.DTLVardef@8f25f9org.highwire.dtl.DTLVardef@63309_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LITDP-43 nuclear depletion causes increased LD, driven by triglyceride accumulation. C_LIO_LITDP-43 nuclear depletion causes increased phagocytosis and pro-inflammatory cytokine expression. C_LIO_LIInhibiting triglyceride synthesis using DGAT inhibitors rescues LD and pro-inflammatory phenotype in TDP-43 depleted MDMi C_LIO_LIALS patient-derived MDMi display increased LD and IL1B expression, rescued by DGAT inhibitors C_LI