Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43
Generation of oligodendrocytes in the adult brain enables both adaptive changes in neural circuits and regeneration of myelin sheaths destroyed by injury, disease, and normal aging. This transformation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes requires processing of...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/75230 |
| _version_ | 1818026584043421696 |
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| author | Dongeun Heo Jonathan P Ling Gian C Molina-Castro Abraham J Langseth Ari Waisman Klaus-Armin Nave Wiebke Möbius Phil C Wong Dwight E Bergles |
| author_facet | Dongeun Heo Jonathan P Ling Gian C Molina-Castro Abraham J Langseth Ari Waisman Klaus-Armin Nave Wiebke Möbius Phil C Wong Dwight E Bergles |
| author_sort | Dongeun Heo |
| collection | DOAJ |
| description | Generation of oligodendrocytes in the adult brain enables both adaptive changes in neural circuits and regeneration of myelin sheaths destroyed by injury, disease, and normal aging. This transformation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes requires processing of distinct mRNAs at different stages of cell maturation. Although mislocalization and aggregation of the RNA-binding protein, TDP-43, occur in both neurons and glia in neurodegenerative diseases, the consequences of TDP-43 loss within different stages of the oligodendrocyte lineage are not well understood. By performing stage-specific genetic inactivation of Tardbp in vivo, we show that oligodendrocyte lineage cells are differentially sensitive to loss of TDP-43. While OPCs depend on TDP-43 for survival, with conditional deletion resulting in cascading cell loss followed by rapid regeneration to restore their density, oligodendrocytes become less sensitive to TDP-43 depletion as they mature. Deletion of TDP-43 early in the maturation process led to eventual oligodendrocyte degeneration, seizures, and premature lethality, while oligodendrocytes that experienced late deletion survived and mice exhibited a normal lifespan. At both stages, TDP-43-deficient oligodendrocytes formed fewer and thinner myelin sheaths and extended new processes that inappropriately wrapped neuronal somata and blood vessels. Transcriptional analysis revealed that in the absence of TDP-43, key proteins involved in oligodendrocyte maturation and myelination were misspliced, leading to aberrant incorporation of cryptic exons. Inducible deletion of TDP-43 from oligodendrocytes in the adult central nervous system (CNS) induced the same progressive morphological changes and mice acquired profound hindlimb weakness, suggesting that loss of TDP-43 function in oligodendrocytes may contribute to neuronal dysfunction in neurodegenerative disease. |
| first_indexed | 2024-12-10T04:34:19Z |
| format | Article |
| id | doaj.art-8e9d240bc0054ec98adfc1e0a0e53006 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T04:34:19Z |
| publishDate | 2022-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-8e9d240bc0054ec98adfc1e0a0e530062022-12-22T02:02:04ZengeLife Sciences Publications LtdeLife2050-084X2022-03-011110.7554/eLife.75230Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43Dongeun Heo0https://orcid.org/0000-0002-4913-2253Jonathan P Ling1https://orcid.org/0000-0003-1927-9729Gian C Molina-Castro2https://orcid.org/0000-0002-0700-4042Abraham J Langseth3Ari Waisman4Klaus-Armin Nave5https://orcid.org/0000-0001-8724-9666Wiebke Möbius6https://orcid.org/0000-0002-2902-7165Phil C Wong7Dwight E Bergles8https://orcid.org/0000-0002-7133-7378The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United StatesThe Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United StatesThe Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United StatesThe Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United StatesInstitute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, GermanyDepartment of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, GermanyDepartment of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany; Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany; Electron Microscopy Core Unit, Max-Planck-Institute of Experimental Medicine, Göttingen, GermanyThe Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United StatesThe Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States; Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, United StatesGeneration of oligodendrocytes in the adult brain enables both adaptive changes in neural circuits and regeneration of myelin sheaths destroyed by injury, disease, and normal aging. This transformation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes requires processing of distinct mRNAs at different stages of cell maturation. Although mislocalization and aggregation of the RNA-binding protein, TDP-43, occur in both neurons and glia in neurodegenerative diseases, the consequences of TDP-43 loss within different stages of the oligodendrocyte lineage are not well understood. By performing stage-specific genetic inactivation of Tardbp in vivo, we show that oligodendrocyte lineage cells are differentially sensitive to loss of TDP-43. While OPCs depend on TDP-43 for survival, with conditional deletion resulting in cascading cell loss followed by rapid regeneration to restore their density, oligodendrocytes become less sensitive to TDP-43 depletion as they mature. Deletion of TDP-43 early in the maturation process led to eventual oligodendrocyte degeneration, seizures, and premature lethality, while oligodendrocytes that experienced late deletion survived and mice exhibited a normal lifespan. At both stages, TDP-43-deficient oligodendrocytes formed fewer and thinner myelin sheaths and extended new processes that inappropriately wrapped neuronal somata and blood vessels. Transcriptional analysis revealed that in the absence of TDP-43, key proteins involved in oligodendrocyte maturation and myelination were misspliced, leading to aberrant incorporation of cryptic exons. Inducible deletion of TDP-43 from oligodendrocytes in the adult central nervous system (CNS) induced the same progressive morphological changes and mice acquired profound hindlimb weakness, suggesting that loss of TDP-43 function in oligodendrocytes may contribute to neuronal dysfunction in neurodegenerative disease.https://elifesciences.org/articles/75230oligodendrocytemyelinALSTDP-43mRNAprogenitor |
| spellingShingle | Dongeun Heo Jonathan P Ling Gian C Molina-Castro Abraham J Langseth Ari Waisman Klaus-Armin Nave Wiebke Möbius Phil C Wong Dwight E Bergles Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43 eLife oligodendrocyte myelin ALS TDP-43 mRNA progenitor |
| title | Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43 |
| title_full | Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43 |
| title_fullStr | Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43 |
| title_full_unstemmed | Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43 |
| title_short | Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43 |
| title_sort | stage specific control of oligodendrocyte survival and morphogenesis by tdp 43 |
| topic | oligodendrocyte myelin ALS TDP-43 mRNA progenitor |
| url | https://elifesciences.org/articles/75230 |
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