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

doi:10.1038/s41593-022-01199-y

. 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 Kalpazidou¹, Christina Koupourtidou^{1

2}, Rico Schieweck¹, Sven Aschenbroich^{1

2}, Lara Silva^{1

4}, Ayse Seda Yazgili^{5

6

7}, Frauke van Bebber⁸, Bettina Schmid⁸, Gabriel Möller⁹, Clara Tritscher⁹, Christian Stigloher⁹, Claire Delbridge¹⁰, Swetlana Sirko^{3

11}, Zeynep Irem Günes¹², Sabine Liebscher^{12

13}, Jürgen Schlegel¹⁰, Hananeh Aliee¹⁴, Fabian Theis¹⁴, Silke Meiners^{5

6

15

16}, Michael Kiebler¹, Dorothee Dormann^#^{1

4

13

17}, Jovica Ninkovic^#^{18

19

20}

Affiliations

¹ Biomedical Center Munich (BMC), Department of Cell Biology and Anatomy, Medical Faculty, LMU, Munich, Germany.
² Graduate School of Systemic Neurosciences, LMU, Munich, Germany.
³ Institute of Stem Cell Research, Helmholtz Zentrum Munich, Munich, Germany.
⁴ Faculty of Biology, Institute of Molecular Physiology, Johannes Gutenberg-Universität (JGU), Mainz, Germany.
⁵ Comprehensive Pneumology Center (CPC), Institute of Lung Health and Immunity (LHI), Helmholtz Zentrum Munich, Munich, Germany.
⁶ Member of the German Center for Lung Research (DZL), Airway Research Center North (ARCN), Grosshansdorf, Germany.
⁷ University Hospital, LMU, Munich, Germany.
⁸ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
⁹ Imaging Core Facility, Biocenter, University of Würzburg, Würzburg, Germany.
¹⁰ Institute of Pathology, Faculty of Medicine, TUM, Munich, Germany.
¹¹ Biomedical Center Munich (BMC), Institute of Physiological Genomics, LMU, Munich, Germany.
¹² Institute of Clinical Neuroimmunology, Klinikum der Universität München, LMU, Munich, Germany.
¹³ Munich Cluster for Systems Neurology SyNergy, LMU, Munich, Germany.
¹⁴ Institute of Computational Biology, Helmholtz Zentrum Munich, Munich, Germany.
¹⁵ Research Center Borstel/Leibniz Lung Center, Borstel, Germany.
¹⁶ Institute of Experimental Medicine, Christian-Albrechts University Kiel, Kiel, Germany.
¹⁷ Institute of Molecular Biology (IMB), Mainz, Germany.
¹⁸ Biomedical Center Munich (BMC), Department of Cell Biology and Anatomy, Medical Faculty, LMU, Munich, Germany. ninkovic@helmholtz-muenchen.de.
¹⁹ Institute of Stem Cell Research, Helmholtz Zentrum Munich, Munich, Germany. ninkovic@helmholtz-muenchen.de.
²⁰ Munich Cluster for Systems Neurology SyNergy, LMU, Munich, Germany. ninkovic@helmholtz-muenchen.de.

^# Contributed equally.

PMID: 36424432
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 et al. Nat Neurosci. 2022 Dec.

. 2022 Dec;25(12):1608-1625.

doi: 10.1038/s41593-022-01199-y. Epub 2022 Nov 24.

Authors

Affiliations

¹ Biomedical Center Munich (BMC), Department of Cell Biology and Anatomy, Medical Faculty, LMU, Munich, Germany.
² Graduate School of Systemic Neurosciences, LMU, Munich, Germany.
³ Institute of Stem Cell Research, Helmholtz Zentrum Munich, Munich, Germany.
⁴ Faculty of Biology, Institute of Molecular Physiology, Johannes Gutenberg-Universität (JGU), Mainz, Germany.
⁵ Comprehensive Pneumology Center (CPC), Institute of Lung Health and Immunity (LHI), Helmholtz Zentrum Munich, Munich, Germany.
⁶ Member of the German Center for Lung Research (DZL), Airway Research Center North (ARCN), Grosshansdorf, Germany.
⁷ University Hospital, LMU, Munich, Germany.
⁸ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
⁹ Imaging Core Facility, Biocenter, University of Würzburg, Würzburg, Germany.
¹⁰ Institute of Pathology, Faculty of Medicine, TUM, Munich, Germany.
¹¹ Biomedical Center Munich (BMC), Institute of Physiological Genomics, LMU, Munich, Germany.
¹² Institute of Clinical Neuroimmunology, Klinikum der Universität München, LMU, Munich, Germany.
¹³ Munich Cluster for Systems Neurology SyNergy, LMU, Munich, Germany.
¹⁴ Institute of Computational Biology, Helmholtz Zentrum Munich, Munich, Germany.
¹⁵ Research Center Borstel/Leibniz Lung Center, Borstel, Germany.
¹⁶ Institute of Experimental Medicine, Christian-Albrechts University Kiel, Kiel, Germany.
¹⁷ Institute of Molecular Biology (IMB), Mainz, Germany.
¹⁸ Biomedical Center Munich (BMC), Department of Cell Biology and Anatomy, Medical Faculty, LMU, Munich, Germany. ninkovic@helmholtz-muenchen.de.
¹⁹ Institute of Stem Cell Research, Helmholtz Zentrum Munich, Munich, Germany. ninkovic@helmholtz-muenchen.de.
²⁰ Munich Cluster for Systems Neurology SyNergy, LMU, Munich, Germany. ninkovic@helmholtz-muenchen.de.

^# Contributed equally.

PMID: 36424432
DOI: 10.1038/s41593-022-01199-y

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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References

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[1] Dimou, L. & Götz, M. Glial cells as progenitors and stem cells: new roles in the healthy and diseased brain. Physiol. Rev. 94, 709–737 (2014). - PubMed

[2] Dimou, L. & Götz, M. Glial cells as progenitors and stem cells: new roles in the healthy and diseased brain. Physiol. Rev. 94, 709–737 (2014). - PubMed

[3] O’Shea, T. M., Burda, J. E. & Sofroniew, M. V. Cell biology of spinal cord injury and repair. J. Clin. Invest. 127, 3259–3270 (2017). - PubMed - PMC

[4] O’Shea, T. M., Burda, J. E. & Sofroniew, M. V. Cell biology of spinal cord injury and repair. J. Clin. Invest. 127, 3259–3270 (2017). - PubMed - PMC

[5] Arvidsson, A., Collin, T., Kirik, D., Kokaia, Z. & Lindvall, O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat. Med. 8, 963–970 (2002). - PubMed

[6] Arvidsson, A., Collin, T., Kirik, D., Kokaia, Z. & Lindvall, O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat. Med. 8, 963–970 (2002). - PubMed

[7] Thored, P. et al. Persistent production of neurons from adult brain stem cells during recovery after stroke. Stem Cells 24, 739–747 (2006). - PubMed

[8] Thored, P. et al. Persistent production of neurons from adult brain stem cells during recovery after stroke. Stem Cells 24, 739–747 (2006). - PubMed

[9] Henriques, D., Moreira, R., Schwamborn, J., Pereira de Almeida, L. & Mendonça, L. S. Successes and hurdles in stem cells application and production for brain transplantation. Front. Neurosci. https://doi.org/10.3389/fnins.2019.01194 (2019).

[10] Henriques, D., Moreira, R., Schwamborn, J., Pereira de Almeida, L. & Mendonça, L. S. Successes and hurdles in stem cells application and production for brain transplantation. Front. Neurosci. https://doi.org/10.3389/fnins.2019.01194 (2019).

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

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

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