{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T22:54:10Z","timestamp":1790463250098,"version":"4.1.0"},"reference-count":57,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,16]],"date-time":"2021-10-16T00:00:00Z","timestamp":1634342400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hualien Tzu Chi Hospital","award":["TC-NHRI106-01 and IMAR-110-01-02"],"award-info":[{"award-number":["TC-NHRI106-01 and IMAR-110-01-02"]}]},{"DOI":"10.13039\/501100006245","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["MOST 107-2314-B-303-001-, MOST 108-2314-B-303-009-, MOST 109-2314-B-303-023-, MOST 110-2314-B-303-025- and MOST 110-2314-B-303 -017 -MY3"],"award-info":[{"award-number":["MOST 107-2314-B-303-001-, MOST 108-2314-B-303-009-, MOST 109-2314-B-303-023-, MOST 110-2314-B-303-025- and MOST 110-2314-B-303 -017 -MY3"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005925","name":"Buddhist Tzu Chi Medical Foundation","doi-asserted-by":"publisher","award":["MF00A130SS01"],"award-info":[{"award-number":["MF00A130SS01"]}],"id":[{"id":"10.13039\/501100005925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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\u2019 MNs, SOD1G85R mutant and corrected SOD1G85G isogenic-induced pluripotent stem cell (iPSC) lines were established. Two SOD1 mutant ALS (SOD1G85R and SOD1D90A), two SOD1 mutant corrected (SOD1G85G and SOD1D90D), and one sporadic ALS iPSC lines were directed toward MNs. After receiving ~90% purity for MNs, we first demonstrated that SOD1G85R mutant ALS MNs recapitulated ALS-specific nerve fiber aggregates, similar to SOD1D90A ALS MNs in a previous study. Moreover, we found that both SOD1 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 Gastrodia elata, showed therapeutic effects that decreased nerve fiber cytopathies and reverse neurotransmitter-induced hyperresponsiveness. The therapeutic effects of gastrodin applied not only to SOD1 ALS MNs but also to sporadic ALS MNs and SOD1G93A ALS mice. Moreover, we found that coactivation of the GSK3\u03b2 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 SOD1 ALS MNs. Interestingly, the therapeutic role of GSK3\u03b2 activation on SOD1 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 GSK3\u03b2 and IGF-1 activation) that may serve as potential targets for ALS therapy.<\/jats:p>","DOI":"10.3390\/cells10102773","type":"journal-article","created":{"date-parts":[[2021,10,17]],"date-time":"2021-10-17T23:13:32Z","timestamp":1634512412000},"page":"2773","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Coactivation of GSK3\u03b2 and IGF-1 Attenuates Amyotrophic Lateral Sclerosis Nerve Fiber Cytopathies in SOD1 Mutant Patient-Derived Motor Neurons"],"prefix":"10.3390","volume":"10","author":[{"given":"Hsiao-Chien","family":"Ting","sequence":"first","affiliation":[{"name":"Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-I","family":"Yang","sequence":"additional","affiliation":[{"name":"Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, Taiwan"},{"name":"Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Horng-Jyh","family":"Harn","sequence":"additional","affiliation":[{"name":"Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, Taiwan"},{"name":"Department of Pathology, Hualien Tzu Chi Hospital and Tzu Chi University, Hualien 97002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6512-9815","authenticated-orcid":false,"given":"Ing-Ming","family":"Chiu","sequence":"additional","affiliation":[{"name":"Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Lin","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Li","sequence":"additional","affiliation":[{"name":"Waisman Center, University of Wisconsin, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-Fang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Hualien Tzu Chi Hospital, Hualien 97002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsung-Jung","family":"Ho","sequence":"additional","affiliation":[{"name":"Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan"},{"name":"Department of Chinese Medicine, Hualien Tzu Chi Hospital, Hualien 97002, Taiwan"},{"name":"Integration Center of Traditional Chinese and Modern Medicine, Hualien Tzu Chi Hospital, Hualien 97002, Taiwan"},{"name":"School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien 97004, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Ann","family":"Liu","sequence":"additional","affiliation":[{"name":"Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, Taiwan"},{"name":"Department of Medical Research, Hualien Tzu Chi Hospital, Hualien 97002, Taiwan"},{"name":"Neuroscience Center, Hualien Tzu Chi Hospital, Hualien 97002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yung-Jen","family":"Tsai","sequence":"additional","affiliation":[{"name":"Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzyy-Wen","family":"Chiou","sequence":"additional","affiliation":[{"name":"Department of Life Science, National Dong Hwa University, Hualien 97441, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinn-Zong","family":"Lin","sequence":"additional","affiliation":[{"name":"Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, Taiwan"},{"name":"Institute of Medical Sciences, Tzu Chi University, Hualien 97004, Taiwan"},{"name":"Department of Neurosurgery, Hualien Tzu Chi Hospital, Hualien 97002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3585-5944","authenticated-orcid":false,"given":"Chia-Yu","family":"Chang","sequence":"additional","affiliation":[{"name":"Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, Taiwan"},{"name":"Department of Medical Research, Hualien Tzu Chi Hospital, Hualien 97002, Taiwan"},{"name":"Neuroscience Center, Hualien Tzu Chi Hospital, Hualien 97002, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nrn3430","article-title":"The changing scene of amyotrophic lateral sclerosis","volume":"14","author":"Robberecht","year":"2013","journal-title":"Nat. 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