n-Butylidenephthalide recovered calcium homeostasis to ameliorate neurodegeneration of motor neurons derived from amyotrophic lateral sclerosis iPSCs.
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that causes muscle atrophy and primarily targets motor neurons (MNs). Approximately 20% of familial ALS cases are caused by gain-of-function mutations in superoxide dismutase 1 (SOD1), leading to MN degeneration and ion ch...
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Public Library of Science (PLoS)
2024-01-01
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| Online Access: | https://doi.org/10.1371/journal.pone.0311573 |
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| author | Yu-Chen Deng Jen-Wei Liu Hsiao-Chien Ting Tzu-Chen Kuo Chia-Hung Chiang En-Yi Lin Horng-Jyh Harn Shinn-Zong Lin Chia-Yu Chang Tzyy-Wen Chiou |
| author_facet | Yu-Chen Deng Jen-Wei Liu Hsiao-Chien Ting Tzu-Chen Kuo Chia-Hung Chiang En-Yi Lin Horng-Jyh Harn Shinn-Zong Lin Chia-Yu Chang Tzyy-Wen Chiou |
| author_sort | Yu-Chen Deng |
| collection | DOAJ |
| description | Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that causes muscle atrophy and primarily targets motor neurons (MNs). Approximately 20% of familial ALS cases are caused by gain-of-function mutations in superoxide dismutase 1 (SOD1), leading to MN degeneration and ion channel dysfunction. Previous studies have shown that n-Butylidenephthalide (BP) delays disease progression and prolongs survival in animal models of ALS. However, no studies have been conducted on models from human sources. Herein, we examined the protective efficacy of BP on MNs derived from induced pluripotent stem cells (iPSCs) of an ALS patient harboring the SOD1G85R mutation as well as on those derived from genetically corrected iPSCs (SOD1G85G). Our results demonstrated that the motor neurons differentiated from iPSC with SOD1G85R mutation exhibited characteristics of neuron degeneration (as indicated by the reduction of neurofilament expression) and ion channel dysfunction (in response to potassium chloride (KCl) and L-glutamate stimulation), in contrast to those derived from the gene corrected iPSC (SOD1G85G). Meanwhile, BP treatment effectively restored calcium ion channel function by reducing the expression of glutamate receptors including glutamate ionotropic receptor AMPA type subunit 3 (GluR3) and glutamate ionotropic receptor NMDA type subunit 1 (NMDAR1). Additionally, BP treatment activated autophagic pathway to attenuate neuron degeneration. Overall, this study supports the therapeutic effects of BP on ALS patient-derived neuron cells, and suggests that BP may be a promising candidate for future drug development. |
| format | Article |
| id | doaj-art-45d92175ece0477197372d69aef19fb2 |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-45d92175ece0477197372d69aef19fb22025-08-20T02:58:10ZengPublic Library of Science (PLoS)PLoS ONE1932-62032024-01-011911e031157310.1371/journal.pone.0311573n-Butylidenephthalide recovered calcium homeostasis to ameliorate neurodegeneration of motor neurons derived from amyotrophic lateral sclerosis iPSCs.Yu-Chen DengJen-Wei LiuHsiao-Chien TingTzu-Chen KuoChia-Hung ChiangEn-Yi LinHorng-Jyh HarnShinn-Zong LinChia-Yu ChangTzyy-Wen ChiouAmyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that causes muscle atrophy and primarily targets motor neurons (MNs). Approximately 20% of familial ALS cases are caused by gain-of-function mutations in superoxide dismutase 1 (SOD1), leading to MN degeneration and ion channel dysfunction. Previous studies have shown that n-Butylidenephthalide (BP) delays disease progression and prolongs survival in animal models of ALS. However, no studies have been conducted on models from human sources. Herein, we examined the protective efficacy of BP on MNs derived from induced pluripotent stem cells (iPSCs) of an ALS patient harboring the SOD1G85R mutation as well as on those derived from genetically corrected iPSCs (SOD1G85G). Our results demonstrated that the motor neurons differentiated from iPSC with SOD1G85R mutation exhibited characteristics of neuron degeneration (as indicated by the reduction of neurofilament expression) and ion channel dysfunction (in response to potassium chloride (KCl) and L-glutamate stimulation), in contrast to those derived from the gene corrected iPSC (SOD1G85G). Meanwhile, BP treatment effectively restored calcium ion channel function by reducing the expression of glutamate receptors including glutamate ionotropic receptor AMPA type subunit 3 (GluR3) and glutamate ionotropic receptor NMDA type subunit 1 (NMDAR1). Additionally, BP treatment activated autophagic pathway to attenuate neuron degeneration. Overall, this study supports the therapeutic effects of BP on ALS patient-derived neuron cells, and suggests that BP may be a promising candidate for future drug development.https://doi.org/10.1371/journal.pone.0311573 |
| spellingShingle | Yu-Chen Deng Jen-Wei Liu Hsiao-Chien Ting Tzu-Chen Kuo Chia-Hung Chiang En-Yi Lin Horng-Jyh Harn Shinn-Zong Lin Chia-Yu Chang Tzyy-Wen Chiou n-Butylidenephthalide recovered calcium homeostasis to ameliorate neurodegeneration of motor neurons derived from amyotrophic lateral sclerosis iPSCs. PLoS ONE |
| title | n-Butylidenephthalide recovered calcium homeostasis to ameliorate neurodegeneration of motor neurons derived from amyotrophic lateral sclerosis iPSCs. |
| title_full | n-Butylidenephthalide recovered calcium homeostasis to ameliorate neurodegeneration of motor neurons derived from amyotrophic lateral sclerosis iPSCs. |
| title_fullStr | n-Butylidenephthalide recovered calcium homeostasis to ameliorate neurodegeneration of motor neurons derived from amyotrophic lateral sclerosis iPSCs. |
| title_full_unstemmed | n-Butylidenephthalide recovered calcium homeostasis to ameliorate neurodegeneration of motor neurons derived from amyotrophic lateral sclerosis iPSCs. |
| title_short | n-Butylidenephthalide recovered calcium homeostasis to ameliorate neurodegeneration of motor neurons derived from amyotrophic lateral sclerosis iPSCs. |
| title_sort | n butylidenephthalide recovered calcium homeostasis to ameliorate neurodegeneration of motor neurons derived from amyotrophic lateral sclerosis ipscs |
| url | https://doi.org/10.1371/journal.pone.0311573 |
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