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A behavior-based drug screening system using a Caenorhabditis elegans model of motor neuron disease

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons, for which there is no effective treatment. Previously, we generated a Caenorhabditis elegans model of ALS, in which the expression of dnc-1, the homologous gene of human d...

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Autores principales: Ikenaka, Kensuke, Tsukada, Yuki, Giles, Andrew C., Arai, Tadamasa, Nakadera, Yasuhito, Nakano, Shunji, Kawai, Kaori, Mochizuki, Hideki, Katsuno, Masahisa, Sobue, Gen, Mori, Ikue
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626054/
https://www.ncbi.nlm.nih.gov/pubmed/31300701
http://dx.doi.org/10.1038/s41598-019-46642-6
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author Ikenaka, Kensuke
Tsukada, Yuki
Giles, Andrew C.
Arai, Tadamasa
Nakadera, Yasuhito
Nakano, Shunji
Kawai, Kaori
Mochizuki, Hideki
Katsuno, Masahisa
Sobue, Gen
Mori, Ikue
author_facet Ikenaka, Kensuke
Tsukada, Yuki
Giles, Andrew C.
Arai, Tadamasa
Nakadera, Yasuhito
Nakano, Shunji
Kawai, Kaori
Mochizuki, Hideki
Katsuno, Masahisa
Sobue, Gen
Mori, Ikue
author_sort Ikenaka, Kensuke
collection PubMed
description Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons, for which there is no effective treatment. Previously, we generated a Caenorhabditis elegans model of ALS, in which the expression of dnc-1, the homologous gene of human dynactin-1, is knocked down (KD) specifically in motor neurons. This dnc-1 KD model showed progressive motor defects together with axonal and neuronal degeneration, as observed in ALS patients. In the present study, we established a behavior-based, automated, and quantitative drug screening system using this dnc-1 KD model together with Multi-Worm Tracker (MWT), and tested whether 38 candidate neuroprotective compounds could improve the mobility of the dnc-1 KD animals. We found that 12 compounds, including riluzole, which is an approved medication for ALS patients, ameliorated the phenotype of the dnc-1 KD animals. Nifedipine, a calcium channel blocker, most robustly ameliorated the motor deficits as well as axonal degeneration of dnc-1 KD animals. Nifedipine also ameliorated the motor defects of other motor neuronal degeneration models of C. elegans, including dnc-1 mutants and human TAR DNA-binding protein of 43 kDa overexpressing worms. Our results indicate that dnc-1 KD in C. elegans is a useful model for the screening of drugs against motor neuron degeneration, and that MWT is a powerful tool for the behavior-based screening of drugs.
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spelling pubmed-66260542019-07-21 A behavior-based drug screening system using a Caenorhabditis elegans model of motor neuron disease Ikenaka, Kensuke Tsukada, Yuki Giles, Andrew C. Arai, Tadamasa Nakadera, Yasuhito Nakano, Shunji Kawai, Kaori Mochizuki, Hideki Katsuno, Masahisa Sobue, Gen Mori, Ikue Sci Rep Article Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons, for which there is no effective treatment. Previously, we generated a Caenorhabditis elegans model of ALS, in which the expression of dnc-1, the homologous gene of human dynactin-1, is knocked down (KD) specifically in motor neurons. This dnc-1 KD model showed progressive motor defects together with axonal and neuronal degeneration, as observed in ALS patients. In the present study, we established a behavior-based, automated, and quantitative drug screening system using this dnc-1 KD model together with Multi-Worm Tracker (MWT), and tested whether 38 candidate neuroprotective compounds could improve the mobility of the dnc-1 KD animals. We found that 12 compounds, including riluzole, which is an approved medication for ALS patients, ameliorated the phenotype of the dnc-1 KD animals. Nifedipine, a calcium channel blocker, most robustly ameliorated the motor deficits as well as axonal degeneration of dnc-1 KD animals. Nifedipine also ameliorated the motor defects of other motor neuronal degeneration models of C. elegans, including dnc-1 mutants and human TAR DNA-binding protein of 43 kDa overexpressing worms. Our results indicate that dnc-1 KD in C. elegans is a useful model for the screening of drugs against motor neuron degeneration, and that MWT is a powerful tool for the behavior-based screening of drugs. Nature Publishing Group UK 2019-07-12 /pmc/articles/PMC6626054/ /pubmed/31300701 http://dx.doi.org/10.1038/s41598-019-46642-6 Text en © The Author(s) 2019 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Ikenaka, Kensuke
Tsukada, Yuki
Giles, Andrew C.
Arai, Tadamasa
Nakadera, Yasuhito
Nakano, Shunji
Kawai, Kaori
Mochizuki, Hideki
Katsuno, Masahisa
Sobue, Gen
Mori, Ikue
A behavior-based drug screening system using a Caenorhabditis elegans model of motor neuron disease
title A behavior-based drug screening system using a Caenorhabditis elegans model of motor neuron disease
title_full A behavior-based drug screening system using a Caenorhabditis elegans model of motor neuron disease
title_fullStr A behavior-based drug screening system using a Caenorhabditis elegans model of motor neuron disease
title_full_unstemmed A behavior-based drug screening system using a Caenorhabditis elegans model of motor neuron disease
title_short A behavior-based drug screening system using a Caenorhabditis elegans model of motor neuron disease
title_sort behavior-based drug screening system using a caenorhabditis elegans model of motor neuron disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626054/
https://www.ncbi.nlm.nih.gov/pubmed/31300701
http://dx.doi.org/10.1038/s41598-019-46642-6
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