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

Alessandro Zambusi; Klara Tereza Novoselc; Saskia Hutten; Sofia Kalpazidou; Christina Koupourtidou; Rico Schieweck; Sven Aschenbroich; Lara Silva; Ayse Seda Yazgili; Frauke van Bebber; Bettina Schmid; Gabriel Möller; Clara Tritscher; Christian Stigloher; Claire Delbridge; Swetlana Sirko; Zeynep Irem Günes; Sabine Liebscher; Jürgen Schlegel; Hananeh Aliee; Fabian Theis; Silke Meiners; Michael Kiebler; Dorothee Dormann; Jovica Ninkovic

doi:10.1038/s41593-022-01199-y

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

Alessandro Zambusi, Klara Tereza Novoselc, Saskia Hutten, Sofia Kalpazidou, Christina Koupourtidou, Rico Schieweck, Sven Aschenbroich, Lara Silva, Ayse Seda Yazgili, Frauke van Bebber, Bettina Schmid, Gabriel Möller, Clara Tritscher, Christian Stigloher, Claire Delbridge, Swetlana Sirko, Zeynep Irem Günes, Sabine Liebscher, Jürgen Schlegel, Hananeh AlieeFabian Theis, Silke Meiners, Michael Kiebler, Dorothee Dormann, Jovica Ninkovic

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23 Scopus citations

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.

Original language	English
Pages (from-to)	1608-1625
Number of pages	18
Journal	Nature Neuroscience
Volume	25
Issue number	12
DOIs	https://doi.org/10.1038/s41593-022-01199-y
State	Published - Dec 2022
Externally published	Yes

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Zambusi, A., Novoselc, K. T., Hutten, S., Kalpazidou, S., Koupourtidou, C., Schieweck, R., Aschenbroich, S., Silva, L., Yazgili, A. S., van Bebber, F., Schmid, B., Möller, G., Tritscher, C., Stigloher, C., Delbridge, C., Sirko, S., Günes, Z. I., Liebscher, S., Schlegel, J., ... Ninkovic, J. (2022). TDP-43 condensates and lipid droplets regulate the reactivity of microglia and regeneration after traumatic brain injury. Nature Neuroscience, 25(12), 1608-1625. https://doi.org/10.1038/s41593-022-01199-y

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

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.",

author = "Alessandro Zambusi and Novoselc, {Klara Tereza} and Saskia Hutten and Sofia Kalpazidou and Christina Koupourtidou and Rico Schieweck and Sven Aschenbroich and Lara Silva and Yazgili, {Ayse Seda} and {van Bebber}, Frauke and Bettina Schmid and Gabriel M{\"o}ller and Clara Tritscher and Christian Stigloher and Claire Delbridge and Swetlana Sirko and G{\"u}nes, {Zeynep Irem} and Sabine Liebscher and J{\"u}rgen Schlegel and Hananeh Aliee and Fabian Theis and Silke Meiners and Michael Kiebler and Dorothee Dormann and Jovica Ninkovic",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = dec,

doi = "10.1038/s41593-022-01199-y",

language = "English",

volume = "25",

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Zambusi, A, Novoselc, KT, Hutten, S, Kalpazidou, S, Koupourtidou, C, Schieweck, R, Aschenbroich, S, Silva, L, Yazgili, AS, van Bebber, F, Schmid, B, Möller, G, Tritscher, C, Stigloher, C, Delbridge, C, Sirko, S, Günes, ZI, Liebscher, S, Schlegel, J, Aliee, H, Theis, F, Meiners, S, Kiebler, M, Dormann, D & Ninkovic, J 2022, 'TDP-43 condensates and lipid droplets regulate the reactivity of microglia and regeneration after traumatic brain injury', Nature Neuroscience, vol. 25, no. 12, pp. 1608-1625. https://doi.org/10.1038/s41593-022-01199-y

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AU - Zambusi, Alessandro

AU - Novoselc, Klara Tereza

AU - Hutten, Saskia

AU - Kalpazidou, Sofia

AU - Koupourtidou, Christina

AU - Schieweck, Rico

AU - Aschenbroich, Sven

AU - Silva, Lara

AU - Yazgili, Ayse Seda

AU - van Bebber, Frauke

AU - Schmid, Bettina

AU - Möller, Gabriel

AU - Tritscher, Clara

AU - Stigloher, Christian

AU - Delbridge, Claire

AU - Sirko, Swetlana

AU - Günes, Zeynep Irem

AU - Liebscher, Sabine

AU - Schlegel, Jürgen

AU - Aliee, Hananeh

AU - Theis, Fabian

AU - Meiners, Silke

AU - Kiebler, Michael

AU - Dormann, Dorothee

AU - Ninkovic, Jovica

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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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U2 - 10.1038/s41593-022-01199-y

DO - 10.1038/s41593-022-01199-y

M3 - Article

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AN - SCOPUS:85142473727

SN - 1097-6256

VL - 25

SP - 1608

EP - 1625

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 12

ER -

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

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