TDP-43 condensates and lipid droplets regulate the reactivity of microglia and regeneration after traumatic brain injury

Decreasing the activation of pathology-activated microglia is crucial to prevent chronic inflammation and tissue scarring. In this study, we used a stab wound injury model in zebrafish and identified an injury-induced microglial state characterized by the accumulation of lipid droplets and TAR DNA-binding protein of 43 kDa (TDP-43)(+) condensates. Granulin-mediated clearance of both lipid droplets and TDP-43(+) condensates was necessary and sufficient to promote the return of microglia back to the basal state and achieve scarless regeneration. Moreover, in postmortem cortical brain tissues from patients with traumatic brain injury, the extent of microglial activation correlated with the accumulation of lipid droplets and TDP-43(+) condensates. Together, our results reveal a mechanism required for restoring microglia to a nonactivated state after injury, which has potential for new therapeutic applications in humans. Zambusi, Novoselc et al. show that granulin-mediated clearance of cytoplasmic TDP-43(+) condensates and lipid droplets in injury-activated microglia is required for their return to the homeostatic state and successful brain regeneration.

Automated summary

The study reveals that clearing lipid droplets and TDP-43(+) condensates is crucial for restoring microglial cells to their nonactivated state and achieving scarless regeneration in zebrafish. The accumulation of these cellular components is also observed in postmortem brain tissues of patients with traumatic brain injury.