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

ABSTRACT: 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-1β production. Inhibiting diacylglycerol acyltransferase (DGAT) enzymes reduced lipid droplet formation, phagocytosis, and IL-1β, directly linking t

SUBMITTER: Kabra K 

PROVIDER: S-EPMC12458125 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature