دورية أكاديمية
Rebalancing the motor circuit restores movement in a Caenorhabditis elegans model for TDP-43 toxicity.
| العنوان: | Rebalancing the motor circuit restores movement in a Caenorhabditis elegans model for TDP-43 toxicity. |
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| المؤلفون: | Koopman M; European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Güngördü L; European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Janssen L; European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Seinstra RI; European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Richmond JE; Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA., Okerlund N; Howard Hughes Medical Institute and School of Biological Science, The University of Utah, Salt Lake City, UT, USA., Wardenaar R; European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Islam P; MRC London Institute of Medical Sciences, London, UK; Institute of Clinical Sciences, Imperial College London, London, UK., Hogewerf W; European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Brown AEX; MRC London Institute of Medical Sciences, London, UK; Institute of Clinical Sciences, Imperial College London, London, UK., Jorgensen EM; Howard Hughes Medical Institute and School of Biological Science, The University of Utah, Salt Lake City, UT, USA., Nollen EAA; European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. Electronic address: e.a.a.nollen@umcg.nl. |
| المصدر: | Cell reports [Cell Rep] 2024 May 28; Vol. 43 (5), pp. 114204. Date of Electronic Publication: 2024 May 14. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 101573691 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2211-1247 (Electronic) NLM ISO Abbreviation: Cell Rep Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [Cambridge, MA] : Cell Press, c 2012- |
| مواضيع طبية MeSH: | Caenorhabditis elegans*/metabolism , DNA-Binding Proteins*/metabolism , DNA-Binding Proteins*/genetics , Disease Models, Animal*, Animals ; GABAergic Neurons/metabolism ; Caenorhabditis elegans Proteins/metabolism ; Caenorhabditis elegans Proteins/genetics ; Motor Neurons/metabolism ; Locomotion ; Synaptic Transmission ; Movement ; Cholinergic Neurons/metabolism |
| مستخلص: | Amyotrophic lateral sclerosis can be caused by abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm of neurons. Here, we use a C. elegans model for TDP-43-induced toxicity to identify the biological mechanisms that lead to disease-related phenotypes. By applying deep behavioral phenotyping and subsequent dissection of the neuromuscular circuit, we show that TDP-43 worms have profound defects in GABA neurons. Moreover, acetylcholine neurons appear functionally silenced. Enhancing functional output of repressed acetylcholine neurons at the level of, among others, G-protein-coupled receptors restores neurotransmission, but inefficiently rescues locomotion. Rebalancing the excitatory-to-inhibitory ratio in the neuromuscular system by simultaneous stimulation of the affected GABA- and acetylcholine neurons, however, not only synergizes the effects of boosting individual neurotransmitter systems, but instantaneously improves movement. Our results suggest that interventions accounting for the altered connectome may be more efficient in restoring motor function than those solely focusing on diseased neuron populations. Competing Interests: Declaration of interests L.J. is currently employed by AstraZeneca as a medical advisor and M.K. is employed by the health insurance company Zilveren Kruis as a data scientist; both positions are unrelated to the current article. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) |
| فهرسة مساهمة: | Keywords: C. elegans; CP: Neuroscience; G-protein coupled receptors; GABA; TDP-43; aceylcholine; amyotrophic lateral sclerosis; connectome; ion channels; neuromuscular junctions; phenomics |
| المشرفين على المادة: | 0 (DNA-Binding Proteins) 0 (Caenorhabditis elegans Proteins) |
| تواريخ الأحداث: | Date Created: 20240515 Date Completed: 20240531 Latest Revision: 20240729 |
| رمز التحديث: | 20240729 |
| DOI: | 10.1016/j.celrep.2024.114204 |
| PMID: | 38748878 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2211-1247 |
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| DOI: | 10.1016/j.celrep.2024.114204 |