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Cell cycle inhibitors protect motor neurons in an organoid model of Spinal Muscular Atrophy

Spinal Muscular Atrophy (SMA) is caused by genetic mutations in the SMN1 gene, resulting in drastically reduced levels of Survival of Motor Neuron (SMN) protein. Although SMN is ubiquitously expressed, spinal motor neurons are one of the most affected cell types. Previous studies have identified pat...

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Autores principales: Hor, Jin Hui, Soh, Eunice Shi-Yi, Tan, Li Yi, Lim, Valerie Jing Wen, Santosa, Munirah Mohamad, Winanto, Ho, Beatrice Xuan, Fan, Yong, Soh, Boon-Seng, Ng, Shi-Yan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204135/
https://www.ncbi.nlm.nih.gov/pubmed/30368521
http://dx.doi.org/10.1038/s41419-018-1081-0
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author Hor, Jin Hui
Soh, Eunice Shi-Yi
Tan, Li Yi
Lim, Valerie Jing Wen
Santosa, Munirah Mohamad
Winanto
Ho, Beatrice Xuan
Fan, Yong
Soh, Boon-Seng
Ng, Shi-Yan
author_facet Hor, Jin Hui
Soh, Eunice Shi-Yi
Tan, Li Yi
Lim, Valerie Jing Wen
Santosa, Munirah Mohamad
Winanto
Ho, Beatrice Xuan
Fan, Yong
Soh, Boon-Seng
Ng, Shi-Yan
author_sort Hor, Jin Hui
collection PubMed
description Spinal Muscular Atrophy (SMA) is caused by genetic mutations in the SMN1 gene, resulting in drastically reduced levels of Survival of Motor Neuron (SMN) protein. Although SMN is ubiquitously expressed, spinal motor neurons are one of the most affected cell types. Previous studies have identified pathways uniquely activated in SMA motor neurons, including a hyperactivated ER stress pathway, neuronal hyperexcitability, and defective spliceosomes. To investigate why motor neurons are more affected than other neural types, we developed a spinal organoid model of SMA. We demonstrate overt motor neuron degeneration in SMA spinal organoids, and this degeneration can be prevented using a small molecule inhibitor of CDK4/6, indicating that spinal organoids are an ideal platform for therapeutic discovery.
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spelling pubmed-62041352018-10-29 Cell cycle inhibitors protect motor neurons in an organoid model of Spinal Muscular Atrophy Hor, Jin Hui Soh, Eunice Shi-Yi Tan, Li Yi Lim, Valerie Jing Wen Santosa, Munirah Mohamad Winanto Ho, Beatrice Xuan Fan, Yong Soh, Boon-Seng Ng, Shi-Yan Cell Death Dis Article Spinal Muscular Atrophy (SMA) is caused by genetic mutations in the SMN1 gene, resulting in drastically reduced levels of Survival of Motor Neuron (SMN) protein. Although SMN is ubiquitously expressed, spinal motor neurons are one of the most affected cell types. Previous studies have identified pathways uniquely activated in SMA motor neurons, including a hyperactivated ER stress pathway, neuronal hyperexcitability, and defective spliceosomes. To investigate why motor neurons are more affected than other neural types, we developed a spinal organoid model of SMA. We demonstrate overt motor neuron degeneration in SMA spinal organoids, and this degeneration can be prevented using a small molecule inhibitor of CDK4/6, indicating that spinal organoids are an ideal platform for therapeutic discovery. Nature Publishing Group UK 2018-10-27 /pmc/articles/PMC6204135/ /pubmed/30368521 http://dx.doi.org/10.1038/s41419-018-1081-0 Text en © The Author(s) 2018 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
Hor, Jin Hui
Soh, Eunice Shi-Yi
Tan, Li Yi
Lim, Valerie Jing Wen
Santosa, Munirah Mohamad
Winanto
Ho, Beatrice Xuan
Fan, Yong
Soh, Boon-Seng
Ng, Shi-Yan
Cell cycle inhibitors protect motor neurons in an organoid model of Spinal Muscular Atrophy
title Cell cycle inhibitors protect motor neurons in an organoid model of Spinal Muscular Atrophy
title_full Cell cycle inhibitors protect motor neurons in an organoid model of Spinal Muscular Atrophy
title_fullStr Cell cycle inhibitors protect motor neurons in an organoid model of Spinal Muscular Atrophy
title_full_unstemmed Cell cycle inhibitors protect motor neurons in an organoid model of Spinal Muscular Atrophy
title_short Cell cycle inhibitors protect motor neurons in an organoid model of Spinal Muscular Atrophy
title_sort cell cycle inhibitors protect motor neurons in an organoid model of spinal muscular atrophy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204135/
https://www.ncbi.nlm.nih.gov/pubmed/30368521
http://dx.doi.org/10.1038/s41419-018-1081-0
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