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The nitroreductase (NTR)\/prodrug system of cell ablation has facilitated investigations of cell function and regeneration but has not been widely adopted as a disease modeling platform, perhaps owing to assumptions that the cell death mechanism(s) elicited is artificial in nature. Prior reports suggested that NTR\/prodrug-mediated death occurred through apoptosis, necroptosis and\/or parthanatos, which have all been implicated in neurodegenerative disease. To clarify this issue, we investigated the cell death pathway(s) elicited by the prodrug metronidazole (MTZ) with improved nitroreductase enzyme variants. We assessed the cell death pathway(s) elicited by NTR 2.0-expressing zebrafish retinal neurons using a transcriptomic analysis, chemical inhibitors and gene-targeting assays. NTR-H, a novel NTR variant, was tested \u2013 and found to be effective \u2013 in human stem cell-derived retinal organoids. Parthanatos was implicated across all conditions tested, while evidence of apoptosis was variable. As parthanatos is associated with neurodegeneration, our results support the use of the NTR\/MTZ system to create inducible neurodegenerative models targeted to specific disease-relevant neuronal cell types.<\/jats:p>","DOI":"10.1242\/dmm.052747","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T18:13:42Z","timestamp":1784916822000},"source":"Crossref","is-referenced-by-count":1,"title":["Cell death analysis of inducible, titratable neurodegenerative disease models in zebrafish and human stem cell-derived retinal organoids"],"prefix":"10.1242","volume":"19","author":[{"given":"Anneliese","family":"Ceisel","sequence":"first","affiliation":[{"name":"Wilmer Eye Institute, Johns Hopkins School of Medicine 1 , Baltimore, MD 21231 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianna","family":"Graziano","sequence":"additional","affiliation":[{"name":"Wilmer Eye Institute, Johns Hopkins School of Medicine 1 , Baltimore, MD 21231 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Emmerich","sequence":"additional","affiliation":[{"name":"Wilmer Eye Institute, Johns Hopkins School of Medicine 1 , Baltimore, MD 21231 ,","place":["USA"]},{"name":"National Heart, Lung and Blood Institute, National Institutes of Health 2 Translational Vascular Medicine Branch , , Bethesda, MD 20814 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangqian","family":"Shi","sequence":"additional","affiliation":[{"name":"Wilmer Eye Institute, Johns Hopkins School of Medicine 1 , Baltimore, MD 21231 ,","place":["USA"]},{"name":"University of Illinois-Chicago 3 Department of Pharmaceutical Sciences , , Chicago, IL 60612 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae-In","family":"Kam","sequence":"additional","affiliation":[{"name":"Institute for Cell Engineering, Johns Hopkins University School of Medicine 4 Neuroregeneration and Stem Cell Programs , , Baltimore, MD 21205 ,","place":["USA"]},{"name":"Johns Hopkins University School of Medicine 5 Department of Neurology , , Baltimore, MD 21205 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Flores-Bellver","sequence":"additional","affiliation":[{"name":"Sue Anschutz-Rodgers Eye Center, University of Colorado Anschutz 6 CellSight Ocular Stem Cell and Regeneration Research Program, Department of Ophthalmology , , Aurora, CO 80045 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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