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

Area of Science:

• Neuroscience
• Immunology
• Metabolic Disease

Background:

• Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss.
• TDP-43 protein pathology is found in over 90% of ALS cases.
• The precise role of microglia, the brain's immune cells, in ALS pathogenesis is not fully understood.

Purpose of the Study:

• To investigate the role of TDP-43 in regulating microglial function.
• To explore the connection between TDP-43, triglyceride metabolism, and microglial activation in ALS.

Main Methods:

• Used shRNA to knockdown TDP-43 (TARDBP) in human monocyte-derived microglia-like cells (MDMi).
• Analyzed changes in lipid metabolism, phagocytosis, and cytokine production (IL-1β).
• Inhibited diacylglycerol acyltransferase (DGAT) enzymes to assess the impact on microglial function.
• Examined patient-derived MDMi from sporadic and TARDBP-mutant ALS cases.

Main Results:

• TDP-43 knockdown in MDMi led to suppressed cholesterol synthesis, increased fatty acid uptake, lipid droplet accumulation, enhanced phagocytosis, and elevated IL-1β production.
• DGAT inhibition reduced lipid droplet formation, phagocytosis, and IL-1β release, confirming the link between triglyceride metabolism and microglial activation.
• Patient-derived ALS cells showed similar alterations, some of which were ameliorated by DGAT inhibition.

Conclusions:

• Dysregulated triglyceride metabolism is a novel pathway through which TDP-43 influences microglial dysfunction in ALS.
• TDP-43's role in regulating microglial lipid metabolism is a potential therapeutic target for ALS.
• Targeting DGAT enzymes may offer a strategy to modulate microglial activity in ALS.