Single-Nucleus RNA Sequencing Reveals the Spatiotemporal Dynamics of Disease-Associated Microglia in Amyotrophic Lateral Sclerosis

This study investigates the role of disease-associated microglia (DAM) in amyotrophic lateral sclerosis (ALS) using a mouse model. It reveals that DAM appear after motor neuron degeneration, primarily in the brain stem and spinal cord, increasing as the disease progresses. The researchers tracked the dynamic transition of homeostatic microglia into DAM and another microglia type called cluster 6, finding that DAM survival is independent of a specific receptor (CSF1R). They also demonstrated that DAM can engulf more particles than other microglia subtypes. The findings suggest that inducing the DAM phenotype early in the disease could be a neuroprotective strategy for ALS. The study identifies a potential therapeutic window between specific disease stages where motor neuron loss slows down.

• 1
  DAM appear after motor neuron degeneration, primarily in the brain stem and spinal cord of ALS mice, and increase in number as the disease progresses, peaking in the late stage.
• 2
  Pseudotime trajectory analysis revealed the dynamic transition of homeostatic microglia into DAM and cluster 6 microglia, indicating distinct pathways of microglial polarization during ALS progression.
• 3
  DAM survival is partially independent of CSF1R, and DAM exhibit an enhanced phagocytic capacity compared to other microglia subtypes, suggesting a specialized role in clearing cellular debris during ALS.