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Human amyotrophic lateral sclerosis excitability phenotype screen: Target discovery and validation
Drug development is hampered by poor target selection. Phenotypic screens using neurons differentiated from patient stem cells offer the possibility to validate known and discover novel disease targets in an unbiased fashion. To identify targets for managing hyperexcitability, a pathological feature...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209673/ https://www.ncbi.nlm.nih.gov/pubmed/34107252 http://dx.doi.org/10.1016/j.celrep.2021.109224 |
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author | Huang, Xuan Roet, Kasper C.D. Zhang, Liying Brault, Amy Berg, Allison P. Jefferson, Anne B. Klug-McLeod, Jackie Leach, Karen L. Vincent, Fabien Yang, Hongying Coyle, Anthony J. Jones, Lyn H. Frost, Devlin Wiskow, Ole Chen, Kuchuan Maeda, Rie Grantham, Alyssa Dornon, Mary K. Klim, Joseph R. Siekmann, Marco T. Zhao, Dongyi Lee, Seungkyu Eggan, Kevin Woolf, Clifford J. |
author_facet | Huang, Xuan Roet, Kasper C.D. Zhang, Liying Brault, Amy Berg, Allison P. Jefferson, Anne B. Klug-McLeod, Jackie Leach, Karen L. Vincent, Fabien Yang, Hongying Coyle, Anthony J. Jones, Lyn H. Frost, Devlin Wiskow, Ole Chen, Kuchuan Maeda, Rie Grantham, Alyssa Dornon, Mary K. Klim, Joseph R. Siekmann, Marco T. Zhao, Dongyi Lee, Seungkyu Eggan, Kevin Woolf, Clifford J. |
author_sort | Huang, Xuan |
collection | PubMed |
description | Drug development is hampered by poor target selection. Phenotypic screens using neurons differentiated from patient stem cells offer the possibility to validate known and discover novel disease targets in an unbiased fashion. To identify targets for managing hyperexcitability, a pathological feature of amyotrophic lateral sclerosis (ALS), we design a multi-step screening funnel using patient-derived motor neurons. High-content live cell imaging is used to evaluate neuronal excitability, and from a screen against a chemogenomic library of 2,899 target-annotated compounds, 67 reduce the hyperexcitability of ALS motor neurons carrying the SOD1(A4V) mutation, without cytotoxicity. Bioinformatic deconvolution identifies 13 targets that modulate motor neuron excitability, including two known ALS excitability modulators, AMPA receptors and Kv7.2/3 ion channels, constituting target validation. We also identify D2 dopamine receptors as modulators of ALS motor neuron excitability. This screen demonstrates the power of human disease cell-based phenotypic screens for identifying clinically relevant targets for neurological disorders. |
format | Online Article Text |
id | pubmed-8209673 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
record_format | MEDLINE/PubMed |
spelling | pubmed-82096732021-06-17 Human amyotrophic lateral sclerosis excitability phenotype screen: Target discovery and validation Huang, Xuan Roet, Kasper C.D. Zhang, Liying Brault, Amy Berg, Allison P. Jefferson, Anne B. Klug-McLeod, Jackie Leach, Karen L. Vincent, Fabien Yang, Hongying Coyle, Anthony J. Jones, Lyn H. Frost, Devlin Wiskow, Ole Chen, Kuchuan Maeda, Rie Grantham, Alyssa Dornon, Mary K. Klim, Joseph R. Siekmann, Marco T. Zhao, Dongyi Lee, Seungkyu Eggan, Kevin Woolf, Clifford J. Cell Rep Article Drug development is hampered by poor target selection. Phenotypic screens using neurons differentiated from patient stem cells offer the possibility to validate known and discover novel disease targets in an unbiased fashion. To identify targets for managing hyperexcitability, a pathological feature of amyotrophic lateral sclerosis (ALS), we design a multi-step screening funnel using patient-derived motor neurons. High-content live cell imaging is used to evaluate neuronal excitability, and from a screen against a chemogenomic library of 2,899 target-annotated compounds, 67 reduce the hyperexcitability of ALS motor neurons carrying the SOD1(A4V) mutation, without cytotoxicity. Bioinformatic deconvolution identifies 13 targets that modulate motor neuron excitability, including two known ALS excitability modulators, AMPA receptors and Kv7.2/3 ion channels, constituting target validation. We also identify D2 dopamine receptors as modulators of ALS motor neuron excitability. This screen demonstrates the power of human disease cell-based phenotypic screens for identifying clinically relevant targets for neurological disorders. 2021-06-08 /pmc/articles/PMC8209673/ /pubmed/34107252 http://dx.doi.org/10.1016/j.celrep.2021.109224 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ). |
spellingShingle | Article Huang, Xuan Roet, Kasper C.D. Zhang, Liying Brault, Amy Berg, Allison P. Jefferson, Anne B. Klug-McLeod, Jackie Leach, Karen L. Vincent, Fabien Yang, Hongying Coyle, Anthony J. Jones, Lyn H. Frost, Devlin Wiskow, Ole Chen, Kuchuan Maeda, Rie Grantham, Alyssa Dornon, Mary K. Klim, Joseph R. Siekmann, Marco T. Zhao, Dongyi Lee, Seungkyu Eggan, Kevin Woolf, Clifford J. Human amyotrophic lateral sclerosis excitability phenotype screen: Target discovery and validation |
title | Human amyotrophic lateral sclerosis excitability phenotype screen: Target discovery and validation |
title_full | Human amyotrophic lateral sclerosis excitability phenotype screen: Target discovery and validation |
title_fullStr | Human amyotrophic lateral sclerosis excitability phenotype screen: Target discovery and validation |
title_full_unstemmed | Human amyotrophic lateral sclerosis excitability phenotype screen: Target discovery and validation |
title_short | Human amyotrophic lateral sclerosis excitability phenotype screen: Target discovery and validation |
title_sort | human amyotrophic lateral sclerosis excitability phenotype screen: target discovery and validation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209673/ https://www.ncbi.nlm.nih.gov/pubmed/34107252 http://dx.doi.org/10.1016/j.celrep.2021.109224 |
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