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

Area of Science:

• Neuroscience
• Immunology
• Metabolic pathways

Background:

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

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.
• To identify potential therapeutic targets within this pathway for ALS treatment.

Main Methods:

• Utilized shRNA-mediated TARDBP knockdown in human monocyte-derived microglia-like cells (MDMi).
• Analyzed gene expression related to cholesterol and fatty acid metabolism.
• Assessed lipid droplet accumulation, phagocytic activity, and IL-1β production.
• Investigated the effects of diacylglycerol acyltransferase (DGAT) enzyme inhibition.
• Compared findings in patient-derived MDMi from sporadic and TARDBP-mutant ALS cases.

Main Results:

• TDP-43 knockdown led to suppressed cholesterol synthesis, increased fatty acid metabolism gene expression, lipid droplet accumulation, enhanced phagocytosis, and elevated IL-1β.
• DGAT inhibition reduced lipid droplet formation, phagocytosis, and IL-1β secretion, confirming the link between triglyceride metabolism and microglial activation.
• ALS patient-derived MDMi exhibited overlapping and distinct metabolic alterations, with some responsive to DGAT inhibition.

Conclusions:

• Dysregulated triglyceride metabolism is a novel mechanism by which TDP-43 influences microglial dysfunction in ALS.
• This study highlights the triglyceride metabolic pathway as a potential therapeutic avenue for ALS.
• Targeting DGAT enzymes may offer a strategy to modulate microglial activity in ALS.