Mis-localization of endogenous TDP-43 leads to ALS-like early-stage metabolic dysfunction and progressive motor deficits
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| Titel: | Mis-localization of endogenous TDP-43 leads to ALS-like early-stage metabolic dysfunction and progressive motor deficits |
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| Autoren: | Yiying Hu, Alexander Hruscha, Chenchen Pan, Martina Schifferer, Michael K. Schmidt, Brigitte Nuscher, Martin Giera, Sarantos Kostidis, Özge Burhan, Frauke van Bebber, Dieter Edbauer, Thomas Arzberger, Christian Haass, Bettina Schmid |
| Quelle: | Mol Neurodegener Molecular Neurodegeneration, Vol 19, Iss 1, Pp 1-23 (2024) Molecular neurodegeneration 19(1), 50 (2024). doi:10.1186/s13024-024-00735-7 |
| Verlagsinformationen: | Springer Science and Business Media LLC, 2024. |
| Publikationsjahr: | 2024 |
| Schlagwörter: | metabolism [Zebrafish Proteins], pathology [Motor Neurons], TDP-43, Hypothalamus, Neuromuscular Junction, metabolism [Neuromuscular Junction], genetics [DNA-Binding Proteins], genetics [Zebrafish Proteins], Zebrafish Proteins/genetics [MeSH], Amyotrophic Lateral Sclerosis/pathology [MeSH], Neuromuscular Junction/pathology [MeSH], Animal model, Zebrafish, Motor Neurons/pathology [MeSH], Neuromuscular Junction/metabolism [MeSH], Amyotrophic Lateral Sclerosis/metabolism [MeSH], Animals [MeSH], DNA-Binding Proteins/genetics [MeSH], Metabolic dysfunction, DNA-Binding Proteins/metabolism [MeSH], Neurodegeneration, Animals, Genetically Modified [MeSH], Zebrafish [MeSH], ALS, Amyotrophic Lateral Sclerosis/genetics [MeSH], Motor Neurons/metabolism [MeSH], Disease Models, Animal [MeSH], Research Article, Zebrafish Proteins/metabolism [MeSH], pathology [Neuromuscular Junction], Animals, Genetically Modified, ddc:570, Tardbp protein, zebrafish, Animals, pathology [Amyotrophic Lateral Sclerosis], RC346-429, Motor Neurons, metabolism [Amyotrophic Lateral Sclerosis], Amyotrophic Lateral Sclerosis, RC952-954.6, metabolism [Motor Neurons], Zebrafish Proteins, DNA-Binding Proteins, genetics [Amyotrophic Lateral Sclerosis], Disease Models, Animal, Geriatrics, Neurology. Diseases of the nervous system, metabolism [DNA-Binding Proteins] |
| Beschreibung: | Background The key pathological signature of ALS/ FTLD is the mis-localization of endogenous TDP-43 from the nucleus to the cytoplasm. However, TDP-43 gain of function in the cytoplasm is still poorly understood since TDP-43 animal models recapitulating mis-localization of endogenous TDP-43 from the nucleus to the cytoplasm are missing. Methods CRISPR/Cas9 technology was used to generate a zebrafish line (called CytoTDP), that mis-locates endogenous TDP-43 from the nucleus to the cytoplasm. Phenotypic characterization of motor neurons and the neuromuscular junction was performed by immunostaining, microglia were immunohistochemically localized by whole-mount tissue clearing and muscle ultrastructure was analyzed by scanning electron microscopy. Behavior was investigated by video tracking and quantitative analysis of swimming parameters. RNA sequencing was used to identify mis-regulated pathways with validation by molecular analysis. Results CytoTDP fish have early larval phenotypes resembling clinical features of ALS such as progressive motor defects, neurodegeneration and muscle atrophy. Taking advantage of zebrafish’s embryonic development that solely relys on yolk usage until 5 days post fertilization, we demonstrated that microglia proliferation and activation in the hypothalamus is independent from food intake. By comparing CytoTDP to a previously generated TDP-43 knockout line, transcriptomic analyses revealed that mis-localization of endogenous TDP-43, rather than TDP-43 nuclear loss of function, leads to early onset metabolic dysfunction. Conclusions The new TDP-43 model mimics the ALS/FTLD hallmark of progressive motor dysfunction. Our results suggest that functional deficits of the hypothalamus, the metabolic regulatory center, might be the primary cause of weight loss in ALS patients. Cytoplasmic gain of function of endogenous TDP-43 leads to metabolic dysfunction in vivo that are reminiscent of early ALS clinical non-motor metabolic alterations. Thus, the CytoTDP zebrafish model offers a unique opportunity to identify mis-regulated targets for therapeutic intervention early in disease progression. |
| Publikationsart: | Article Other literature type |
| Dateibeschreibung: | application/pdf |
| Sprache: | English |
| ISSN: | 1750-1326 |
| DOI: | 10.1186/s13024-024-00735-7 |
| Zugangs-URL: | https://pubmed.ncbi.nlm.nih.gov/38902734 https://doaj.org/article/3a903ab063944d74afd22278e76a4d88 https://hdl.handle.net/1887/4089826 https://repository.publisso.de/resource/frl:6499363 https://epub.ub.uni-muenchen.de/122904/ |
| Rights: | CC BY URL: http://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (http://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (http://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
| Dokumentencode: | edsair.doi.dedup.....31777b8d5d2e038eadfdc83e3e9bae84 |
| Datenbank: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstract: | Background The key pathological signature of ALS/ FTLD is the mis-localization of endogenous TDP-43 from the nucleus to the cytoplasm. However, TDP-43 gain of function in the cytoplasm is still poorly understood since TDP-43 animal models recapitulating mis-localization of endogenous TDP-43 from the nucleus to the cytoplasm are missing. Methods CRISPR/Cas9 technology was used to generate a zebrafish line (called CytoTDP), that mis-locates endogenous TDP-43 from the nucleus to the cytoplasm. Phenotypic characterization of motor neurons and the neuromuscular junction was performed by immunostaining, microglia were immunohistochemically localized by whole-mount tissue clearing and muscle ultrastructure was analyzed by scanning electron microscopy. Behavior was investigated by video tracking and quantitative analysis of swimming parameters. RNA sequencing was used to identify mis-regulated pathways with validation by molecular analysis. Results CytoTDP fish have early larval phenotypes resembling clinical features of ALS such as progressive motor defects, neurodegeneration and muscle atrophy. Taking advantage of zebrafish’s embryonic development that solely relys on yolk usage until 5 days post fertilization, we demonstrated that microglia proliferation and activation in the hypothalamus is independent from food intake. By comparing CytoTDP to a previously generated TDP-43 knockout line, transcriptomic analyses revealed that mis-localization of endogenous TDP-43, rather than TDP-43 nuclear loss of function, leads to early onset metabolic dysfunction. Conclusions The new TDP-43 model mimics the ALS/FTLD hallmark of progressive motor dysfunction. Our results suggest that functional deficits of the hypothalamus, the metabolic regulatory center, might be the primary cause of weight loss in ALS patients. Cytoplasmic gain of function of endogenous TDP-43 leads to metabolic dysfunction in vivo that are reminiscent of early ALS clinical non-motor metabolic alterations. Thus, the CytoTDP zebrafish model offers a unique opportunity to identify mis-regulated targets for therapeutic intervention early in disease progression. |
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| ISSN: | 17501326 |
| DOI: | 10.1186/s13024-024-00735-7 |