Coactivation of GSK3β and IGF-1 Attenuates Amyotrophic Lateral Sclerosis Nerve Fiber Cytopathies in SOD1 Mutant Patient-Derived Motor Neurons
Amyotrophic lateral sclerosis (ALS) is a progressive nervous system disease that causes motor neuron (MN) degeneration and results in patient death within a few years. To recapitulate the cytopathies of ALS patients’ MNs, <i>SOD1</i><sup>G85R</sup> mutant and corrected <i&...
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MDPI AG
2021-10-01
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| author | Hsiao-Chien Ting Hui-I Yang Horng-Jyh Harn Ing-Ming Chiu Hong-Lin Su Xiang Li Mei-Fang Chen Tsung-Jung Ho Ching-Ann Liu Yung-Jen Tsai Tzyy-Wen Chiou Shinn-Zong Lin Chia-Yu Chang |
| author_facet | Hsiao-Chien Ting Hui-I Yang Horng-Jyh Harn Ing-Ming Chiu Hong-Lin Su Xiang Li Mei-Fang Chen Tsung-Jung Ho Ching-Ann Liu Yung-Jen Tsai Tzyy-Wen Chiou Shinn-Zong Lin Chia-Yu Chang |
| author_sort | Hsiao-Chien Ting |
| collection | DOAJ |
| description | Amyotrophic lateral sclerosis (ALS) is a progressive nervous system disease that causes motor neuron (MN) degeneration and results in patient death within a few years. To recapitulate the cytopathies of ALS patients’ MNs, <i>SOD1</i><sup>G85R</sup> mutant and corrected <i>SOD1</i><sup>G85G</sup> isogenic-induced pluripotent stem cell (iPSC) lines were established. Two <i>SOD1</i> mutant ALS (<i>SOD1<sup>G85R</sup></i> and <i>SOD1</i><sup>D90A</sup>), two <i>SOD1</i> mutant corrected (<i>SOD1</i><sup>G85G</sup> and <i>SOD1</i><sup>D90D</sup>), and one sporadic ALS iPSC lines were directed toward MNs. After receiving ~90% purity for MNs, we first demonstrated that <i>SOD1</i><sup>G85R</sup> mutant ALS MNs recapitulated ALS-specific nerve fiber aggregates, similar to <i>SOD1</i><sup>D90A</sup> ALS MNs in a previous study. Moreover, we found that both <i>SOD1</i> mutant MNs showed ALS-specific neurite degenerations and neurotransmitter-induced calcium hyperresponsiveness. In a small compound test using these MNs, we demonstrated that gastrodin, a major ingredient of <i>Gastrodia elata</i>, showed therapeutic effects that decreased nerve fiber cytopathies and reverse neurotransmitter-induced hyperresponsiveness. The therapeutic effects of gastrodin applied not only to <i>SOD1</i> ALS MNs but also to sporadic ALS MNs and <i>SOD1</i><sup>G93A</sup> ALS mice. Moreover, we found that coactivation of the GSK3β and IGF-1 pathways was a mechanism involved in the therapeutic effects of gastrodin. Thus, the coordination of compounds that activate these two mechanisms could reduce nerve fiber cytopathies in <i>SOD1</i> ALS MNs. Interestingly, the therapeutic role of GSK3β activation on <i>SOD1</i> ALS MNs in the present study was in contrast to the role previously reported in research using cell line- or transgenic animal-based models. In conclusion, we identified in vitro ALS-specific nerve fiber and neurofunctional markers in MNs, which will be useful for drug screening, and we used an iPSC-based model to reveal novel therapeutic mechanisms (including GSK3β and IGF-1 activation) that may serve as potential targets for ALS therapy. |
| first_indexed | 2024-03-10T06:39:46Z |
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| last_indexed | 2024-03-10T06:39:46Z |
| publishDate | 2021-10-01 |
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| series | Cells |
| spelling | doaj.art-abab29275a294e7fb33d554bb1be9bcf2023-11-22T17:48:57ZengMDPI AGCells2073-44092021-10-011010277310.3390/cells10102773Coactivation of GSK3β and IGF-1 Attenuates Amyotrophic Lateral Sclerosis Nerve Fiber Cytopathies in SOD1 Mutant Patient-Derived Motor NeuronsHsiao-Chien Ting0Hui-I Yang1Horng-Jyh Harn2Ing-Ming Chiu3Hong-Lin Su4Xiang Li5Mei-Fang Chen6Tsung-Jung Ho7Ching-Ann Liu8Yung-Jen Tsai9Tzyy-Wen Chiou10Shinn-Zong Lin11Chia-Yu Chang12Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, TaiwanBioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, TaiwanBioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, TaiwanInstitute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, TaiwanDepartment of Life Sciences, National Chung Hsing University, Taichung 40227, TaiwanWaisman Center, University of Wisconsin, Madison, WI 53705, USADepartment of Medical Research, Hualien Tzu Chi Hospital, Hualien 97002, TaiwanInstitute of Medical Sciences, Tzu Chi University, Hualien 97004, TaiwanBioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, TaiwanBioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, TaiwanDepartment of Life Science, National Dong Hwa University, Hualien 97441, TaiwanBioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, TaiwanBioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, TaiwanAmyotrophic lateral sclerosis (ALS) is a progressive nervous system disease that causes motor neuron (MN) degeneration and results in patient death within a few years. To recapitulate the cytopathies of ALS patients’ MNs, <i>SOD1</i><sup>G85R</sup> mutant and corrected <i>SOD1</i><sup>G85G</sup> isogenic-induced pluripotent stem cell (iPSC) lines were established. Two <i>SOD1</i> mutant ALS (<i>SOD1<sup>G85R</sup></i> and <i>SOD1</i><sup>D90A</sup>), two <i>SOD1</i> mutant corrected (<i>SOD1</i><sup>G85G</sup> and <i>SOD1</i><sup>D90D</sup>), and one sporadic ALS iPSC lines were directed toward MNs. After receiving ~90% purity for MNs, we first demonstrated that <i>SOD1</i><sup>G85R</sup> mutant ALS MNs recapitulated ALS-specific nerve fiber aggregates, similar to <i>SOD1</i><sup>D90A</sup> ALS MNs in a previous study. Moreover, we found that both <i>SOD1</i> mutant MNs showed ALS-specific neurite degenerations and neurotransmitter-induced calcium hyperresponsiveness. In a small compound test using these MNs, we demonstrated that gastrodin, a major ingredient of <i>Gastrodia elata</i>, showed therapeutic effects that decreased nerve fiber cytopathies and reverse neurotransmitter-induced hyperresponsiveness. The therapeutic effects of gastrodin applied not only to <i>SOD1</i> ALS MNs but also to sporadic ALS MNs and <i>SOD1</i><sup>G93A</sup> ALS mice. Moreover, we found that coactivation of the GSK3β and IGF-1 pathways was a mechanism involved in the therapeutic effects of gastrodin. Thus, the coordination of compounds that activate these two mechanisms could reduce nerve fiber cytopathies in <i>SOD1</i> ALS MNs. Interestingly, the therapeutic role of GSK3β activation on <i>SOD1</i> ALS MNs in the present study was in contrast to the role previously reported in research using cell line- or transgenic animal-based models. In conclusion, we identified in vitro ALS-specific nerve fiber and neurofunctional markers in MNs, which will be useful for drug screening, and we used an iPSC-based model to reveal novel therapeutic mechanisms (including GSK3β and IGF-1 activation) that may serve as potential targets for ALS therapy.https://www.mdpi.com/2073-4409/10/10/2773amyotrophic lateral sclerosis (ALS)induced pluripotent stem cell (iPSC)motor neuron (MN)<i>SOD1</i>drug screeninggastrodin |
| spellingShingle | Hsiao-Chien Ting Hui-I Yang Horng-Jyh Harn Ing-Ming Chiu Hong-Lin Su Xiang Li Mei-Fang Chen Tsung-Jung Ho Ching-Ann Liu Yung-Jen Tsai Tzyy-Wen Chiou Shinn-Zong Lin Chia-Yu Chang Coactivation of GSK3β and IGF-1 Attenuates Amyotrophic Lateral Sclerosis Nerve Fiber Cytopathies in SOD1 Mutant Patient-Derived Motor Neurons Cells amyotrophic lateral sclerosis (ALS) induced pluripotent stem cell (iPSC) motor neuron (MN) <i>SOD1</i> drug screening gastrodin |
| title | Coactivation of GSK3β and IGF-1 Attenuates Amyotrophic Lateral Sclerosis Nerve Fiber Cytopathies in SOD1 Mutant Patient-Derived Motor Neurons |
| title_full | Coactivation of GSK3β and IGF-1 Attenuates Amyotrophic Lateral Sclerosis Nerve Fiber Cytopathies in SOD1 Mutant Patient-Derived Motor Neurons |
| title_fullStr | Coactivation of GSK3β and IGF-1 Attenuates Amyotrophic Lateral Sclerosis Nerve Fiber Cytopathies in SOD1 Mutant Patient-Derived Motor Neurons |
| title_full_unstemmed | Coactivation of GSK3β and IGF-1 Attenuates Amyotrophic Lateral Sclerosis Nerve Fiber Cytopathies in SOD1 Mutant Patient-Derived Motor Neurons |
| title_short | Coactivation of GSK3β and IGF-1 Attenuates Amyotrophic Lateral Sclerosis Nerve Fiber Cytopathies in SOD1 Mutant Patient-Derived Motor Neurons |
| title_sort | coactivation of gsk3β and igf 1 attenuates amyotrophic lateral sclerosis nerve fiber cytopathies in sod1 mutant patient derived motor neurons |
| topic | amyotrophic lateral sclerosis (ALS) induced pluripotent stem cell (iPSC) motor neuron (MN) <i>SOD1</i> drug screening gastrodin |
| url | https://www.mdpi.com/2073-4409/10/10/2773 |
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