{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T11:46:57Z","timestamp":1789991217500,"version":"4.0.1"},"reference-count":25,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2019,6,21]],"date-time":"2019-06-21T00:00:00Z","timestamp":1561075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The mitochondrial genetic disorder, Leber\u2019s hereditary optic neuropathy (LHON), is caused by a mutation in MT-ND4 gene, encoding NADH dehydrogenase subunit 4. It leads to the progressive death of retinal ganglion cells (RGCs) and causes visual impairment or even blindness. However, the precise mechanisms of LHON disease penetrance and progression are not completely elucidated. Human-induced pluripotent stem cells (hiPSCs) offer unique opportunities to investigate disease-relevant phenotypes and regulatory mechanisms underlying LHON pathogenesis at the cellular level. In this study, we successfully generated RGCs by differentiation of LHON patient-specific hiPSCs. We modified the protocol of differentiation to obtain a more enriched population of single-cell RGCs for LHON study. Based on assessing morphology, expression of specific markers and electrophysiological activity, we found that LHON-specific hiPSC-derived were more defective in comparison with normal wild-type RGCs. Based on our previous study, whereby by using microarray analysis we identified that the components of glutamatergic synapse signaling pathway were significantly downregulated in LHON-specific RGCs, we focused our study on glutamate-associated \u03b1-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. We found that the protein expression levels of the subunits of the AMPA receptor, GluR1 and GluR2, and their associated scaffold proteins were decreased in LHON-RGCs. By performing the co-immunoprecipitation assay, we found several differences in the efficiencies of interaction between AMPA subunits and scaffold proteins between normal and LHON-specific RGCs.<\/jats:p>","DOI":"10.3390\/cells8060625","type":"journal-article","created":{"date-parts":[[2019,6,21]],"date-time":"2019-06-21T11:54:31Z","timestamp":1561118071000},"page":"625","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Glutamate Stimulation Dysregulates AMPA Receptors-Induced Signal Transduction Pathway in Leber\u2019s Inherited Optic Neuropathy Patient-Specific hiPSC-Derived Retinal Ganglion Cells"],"prefix":"10.3390","volume":"8","author":[{"given":"Yi-Ping","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan"},{"name":"School of Medicine, National Yang-Ming University, Taipei 112, Taiwan"},{"name":"School of Pharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phan Nguyen Nhi","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Cancer Center, Taipei Veterans General Hospital, Taipei 112, Taiwan"},{"name":"Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tai-Chi","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Medicine, National Yang-Ming University, Taipei 112, Taiwan"},{"name":"Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan"},{"name":"Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aliaksandr A.","family":"Yarmishyn","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan"},{"name":"Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wun-Syuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"De-Kuang","family":"Hwang","sequence":"additional","affiliation":[{"name":"School of Medicine, National Yang-Ming University, Taipei 112, Taiwan"},{"name":"Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan"},{"name":"Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang-Yuh","family":"Chiou","sequence":"additional","affiliation":[{"name":"Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu 300, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Wei","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9666-1273","authenticated-orcid":false,"given":"Chian-Shiu","family":"Chien","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan"},{"name":"Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Yao","family":"Tsai","sequence":"additional","affiliation":[{"name":"School of Medicine, National Yang-Ming University, Taipei 112, Taiwan"},{"name":"Department of Ophthalmology, Taipei City Hospital, Taipei 103, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Hwa","family":"Chiou","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan"},{"name":"Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan"},{"name":"Genomic Research Center, Academia Sinica, Taipei 115, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Jen","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medicine, National Yang-Ming University, Taipei 112, Taiwan"},{"name":"Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Hsien","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan"},{"name":"Department of Ophthalmology, Fu-Jen Catholic University, Taipei 242, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2354-2999","authenticated-orcid":false,"given":"Chih-Chien","family":"Hsu","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan"},{"name":"Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,21]]},"reference":[{"key":"ref_1","first-page":"481","article-title":"Primary pathogenic mtdna mutations in multigeneration pedigrees with leber hereditary optic neuropathy","volume":"59","author":"Mackey","year":"1996","journal-title":"Am. 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