{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T07:51:19Z","timestamp":1782978679419,"version":"3.54.5"},"reference-count":37,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T00:00:00Z","timestamp":1686009600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006312","name":"BrightFocus Foundation","doi-asserted-by":"publisher","award":["G2019302"],"award-info":[{"award-number":["G2019302"]}],"id":[{"id":"10.13039\/100006312","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006312","name":"BrightFocus Foundation","doi-asserted-by":"publisher","award":["R01EY019949"],"award-info":[{"award-number":["R01EY019949"]}],"id":[{"id":"10.13039\/100006312","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006312","name":"BrightFocus Foundation","doi-asserted-by":"publisher","award":["R01EY025061"],"award-info":[{"award-number":["R01EY025061"]}],"id":[{"id":"10.13039\/100006312","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006312","name":"BrightFocus Foundation","doi-asserted-by":"publisher","award":["EY030970"],"award-info":[{"award-number":["EY030970"]}],"id":[{"id":"10.13039\/100006312","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006312","name":"BrightFocus Foundation","doi-asserted-by":"publisher","award":["R01EY020545"],"award-info":[{"award-number":["R01EY020545"]}],"id":[{"id":"10.13039\/100006312","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006312","name":"BrightFocus Foundation","doi-asserted-by":"publisher","award":["R01EY029705"],"award-info":[{"award-number":["R01EY029705"]}],"id":[{"id":"10.13039\/100006312","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Eye Institute (NEI)","award":["G2019302"],"award-info":[{"award-number":["G2019302"]}]},{"name":"National Eye Institute (NEI)","award":["R01EY019949"],"award-info":[{"award-number":["R01EY019949"]}]},{"name":"National Eye Institute (NEI)","award":["R01EY025061"],"award-info":[{"award-number":["R01EY025061"]}]},{"name":"National Eye Institute (NEI)","award":["EY030970"],"award-info":[{"award-number":["EY030970"]}]},{"name":"National Eye Institute (NEI)","award":["R01EY020545"],"award-info":[{"award-number":["R01EY020545"]}]},{"name":"National Eye Institute (NEI)","award":["R01EY029705"],"award-info":[{"award-number":["R01EY029705"]}]},{"name":"Department of Ophthalmology, the State University of New York at Buffalo","award":["G2019302"],"award-info":[{"award-number":["G2019302"]}]},{"name":"Department of Ophthalmology, the State University of New York at Buffalo","award":["R01EY019949"],"award-info":[{"award-number":["R01EY019949"]}]},{"name":"Department of Ophthalmology, the State University of New York at Buffalo","award":["R01EY025061"],"award-info":[{"award-number":["R01EY025061"]}]},{"name":"Department of Ophthalmology, the State University of New York at Buffalo","award":["EY030970"],"award-info":[{"award-number":["EY030970"]}]},{"name":"Department of Ophthalmology, the State University of New York at Buffalo","award":["R01EY020545"],"award-info":[{"award-number":["R01EY020545"]}]},{"name":"Department of Ophthalmology, the State University of New York at Buffalo","award":["R01EY029705"],"award-info":[{"award-number":["R01EY029705"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>p58IPK is a multifaceted endoplasmic reticulum (ER) chaperone and a regulator of eIF2\u03b1 kinases involved in a wide range of cellular processes including protein synthesis, ER stress response, and macrophage-mediated inflammation. Systemic deletion of p58IPK leads to age-related loss of retinal ganglion cells (RGC) and exacerbates RGC damage induced by ischemia\/reperfusion and increased intraocular pressure (IOP), suggesting a protective role of p58IPK in the retina. However, the mechanisms remain elusive. Herein, we investigated the cellular mechanisms underlying the neuroprotection action of p58IPK using conditional knockout (cKO) mouse lines where p58IPK is deleted in retinal neurons (Chx10-p58IPK cKO) or in myeloid cells (Lyz2-p58IPK cKO). In addition, we overexpressed p58IPK by adeno-associated virus (AAV) in the retina to examine the effect of p58IPK on RGC survival after ocular hypertension (OHT) in wild type (WT) mice. Our results show that overexpression of p58IPK by AAV significantly improved RGC survival after OHT in WT mice, suggesting a protective effect of p58IPK on reducing RGC injury. Conditional knockout of p58IPK in retinal neurons or in myeloid cells did not alter retinal structure or cellular composition. However, a significant reduction in the b wave of light-adapted electroretinogram (ERG) was observed in Chx10-p58IPK cKO mice. Deletion of p58IPK in retinal neurons exacerbates RGC loss at 14 days after OHT. In contrast, deficiency of p58IPK in myeloid cells increased the microglia\/macrophage activation but had no effect on RGC loss. We conclude that deletion of p58IPK in macrophages increases their activation, but does not influence RGC survival. These results suggest that the neuroprotective action of p58IPK is mediated by its expression in retinal neurons, but not in macrophages. Therefore, targeting p58IPK specifically in retinal neurons is a promising approach for the treatment of neurodegenerative retinal diseases including glaucoma.<\/jats:p>","DOI":"10.3390\/cells12121558","type":"journal-article","created":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T02:08:15Z","timestamp":1686017295000},"page":"1558","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Neuronal p58IPK Protects Retinal Ganglion Cells Independently of Macrophage\/Microglia Activation in Ocular Hypertension"],"prefix":"10.3390","volume":"12","author":[{"given":"Todd","family":"McLaughlin","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2541-7622","authenticated-orcid":false,"given":"Jinli","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyun","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA"},{"name":"Beijing Tongren Hospital, Capital Medical University, Beijing 100005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuguo","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA"},{"name":"Taihe Hospital, Hubei University of Medicine, Shiyan 442005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua J.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8003-7529","authenticated-orcid":false,"given":"Xiuqian","family":"Mu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA"},{"name":"Department of Biochemistry, University at Buffalo, State University of New York, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah X.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA"},{"name":"Department of Biochemistry, University at Buffalo, State University of New York, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1146\/annurev-vision-102016-061422","article-title":"Neuroprotection in Glaucoma: Animal Models and Clinical Trials","volume":"3","author":"Almasieh","year":"2017","journal-title":"Annu. 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Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Coyle, S., Khan, M.N., Chemaly, M., Callaghan, B., Doyle, C., Willoughby, C.E., Atkinson, S.D., Gregory-Ksander, M., and McGilligan, V. (2021). Targeting the NLRP3 Inflammasome in Glaucoma. Biomolecules, 11.","DOI":"10.3390\/biom11081239"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s13024-022-00528-w","article-title":"Cellular stress signaling and the unfolded protein response in retinal degeneration: Mechanisms and therapeutic implications","volume":"17","author":"McLaughlin","year":"2022","journal-title":"Mol. Neurodegener."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"15558","DOI":"10.1074\/jbc.M212074200","article-title":"P58IPK, a Novel Endoplasmic Reticulum Stress-inducible Protein and Potential Negative Regulator of eIF2\u03b1 Signaling","volume":"278","author":"Martindale","year":"2003","journal-title":"J. Biol. 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