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However, the pathological mechanisms of RGC degeneration are not completely understood. Here, we investigated the role of chronic endoplasmic reticulum (ER) stress in glaucomatous neurodegeneration. To evaluate whether chronic ER stress-induced transcriptional factors, activating transcription factor 4 (ATF4), and C\/EBP homologous protein (CHOP) are induced in RGCs; we utilized human donor tissue and the microbead occlusion model of glaucoma. Additionally, we performed the intravitreal injection of adeno-associated virus (AAV) 2 to express CHOP selectively in RGCs in C57BL\/6 mice and evaluated its effect on RGC function and structure by pattern electroretinogram (PERG) and whole-mount retina staining with the RBPMS antibody. Here, we report that the ATF4-CHOP pathway is activated in the retinas of human glaucoma donor eyes and a mouse model of ocular hypertension. Further, the expression of CHOP in RGCs led to a significant loss of function, as evidenced by reduced PERG. Notably, the expression of CHOP in the retina induced a significant structural loss of RGCs within 15 weeks of injection. Altogether, our studies indicate that the expression of CHOP in RGCs leads to neurodegeneration in mice.<\/jats:p>","DOI":"10.3390\/ijms26051858","type":"journal-article","created":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T07:53:06Z","timestamp":1740124386000},"page":"1858","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["C\/EBP Homologous Protein Expression in Retinal Ganglion Cells Induces Neurodegeneration in Mice"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0303-6124","authenticated-orcid":false,"given":"William C.","family":"Mayhew","sequence":"first","affiliation":[{"name":"North Texas Eye Research Institute, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balasankara Reddy","family":"Kaipa","sequence":"additional","affiliation":[{"name":"Gavin Herbert Eye Institute-Center for Translational Vision Research, Department of Ophthalmology, University of California Irvine School of Medicine, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linya","family":"Li","sequence":"additional","affiliation":[{"name":"Gavin Herbert Eye Institute-Center for Translational Vision Research, Department of Ophthalmology, University of California Irvine School of Medicine, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prabhavathi","family":"Maddineni","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yogapriya","family":"Sundaresan","sequence":"additional","affiliation":[{"name":"Gavin Herbert Eye Institute-Center for Translational Vision Research, Department of Ophthalmology, University of California Irvine School of Medicine, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3594-6560","authenticated-orcid":false,"given":"Abbot F.","family":"Clark","sequence":"additional","affiliation":[{"name":"North Texas Eye Research Institute, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9472-9373","authenticated-orcid":false,"given":"Gulab S.","family":"Zode","sequence":"additional","affiliation":[{"name":"Gavin Herbert Eye Institute-Center for Translational Vision Research, Department of Ophthalmology, University of California Irvine School of Medicine, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2635","DOI":"10.1167\/iovs.17-23434","article-title":"Proteomic Alterations in Aqueous Humor From Patients With Primary Open Angle Glaucoma","volume":"59","author":"Sharma","year":"2018","journal-title":"Investig. 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