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. 2022 Dec;25(12):1608-1625.
doi: 10.1038/s41593-022-01199-y. Epub 2022 Nov 24.

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

Alessandro Zambusi #  1   2   3 , Klara Tereza Novoselc #  1   2   3 , Saskia Hutten  1   4 , Sofia Kalpazidou  1 , Christina Koupourtidou  1   2 , Rico Schieweck  1 , Sven Aschenbroich  1   2 , Lara Silva  1   4 , Ayse Seda Yazgili  5   6   7 , Frauke van Bebber  8 , Bettina Schmid  8 , Gabriel Möller  9 , Clara Tritscher  9 , Christian Stigloher  9 , Claire Delbridge  10 , Swetlana Sirko  3   11 , Zeynep Irem Günes  12 , Sabine Liebscher  12   13 , Jürgen Schlegel  10 , Hananeh Aliee  14 , Fabian Theis  14 , Silke Meiners  5   6   15   16 , Michael Kiebler  1 , Dorothee Dormann #  1   4   13   17 , Jovica Ninkovic #  18   19   20
Affiliations

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

Alessandro Zambusi et al. Nat Neurosci. 2022 Dec.

Abstract

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.

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