{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:01:17Z","timestamp":1782280877220,"version":"3.54.5"},"posted":{"date-parts":[[2025,6,6]]},"group-title":"Cell Biology","reference-count":93,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T00:00:00Z","timestamp":1749168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"crossref","award":["EY012910"],"award-info":[{"award-number":["EY012910"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001209","name":"Knights Templar Eye Foundation","doi-asserted-by":"crossref","award":["2024-40"],"award-info":[{"award-number":["2024-40"]}],"id":[{"id":"10.13039\/100001209","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Early-onset inherited retinal degenerations (IRDs), such as Leber congenital amaurosis (LCA) caused by pathogenic variants in the\n                  <jats:italic>NMNAT1<\/jats:italic>\n                  gene, lead to severe vision loss in children. Despite its ubiquitous expression, reduced\n                  <jats:italic>NMNAT1<\/jats:italic>\n                  function primarily affects photoreceptor cells (PRs) of the retina, yet the mechanisms underlying their heightened vulnerability remain incompletely understood. Here, we demonstrate that reduced NMNAT1 enzyme function due to the p.V9M mutation leads to DNA damage in PRs, characterized by the progressive accumulation of the oxidative DNA adduct 8-oxo-dG in\n                  <jats:italic>Nmnat1<\/jats:italic>\n                  <jats:sup>V9M\/V9M<\/jats:sup>\n                  mutant mice. Cells with oxidative DNA damage also demonstrate DNA double-strand breaks, as evidenced by co-staining with antibodies to phosphorylated H2AX (\u03b3H2A.X). This DNA damage correlates with apoptosis-driven PR degeneration, as evidenced by caspase-9 activation and TUNEL staining in the PRs of the\n                  <jats:italic>Nmnat1<\/jats:italic>\n                  <jats:sup>V9M\/V9M<\/jats:sup>\n                  mutant mice, while alternative cell death pathways such as necroptosis and parthanatos were not significantly activated. Treatment with the antioxidant N-acetylcysteine (NAC) effectively reduced oxidative DNA damage and retinal immune responses, mitigated apoptosis, and preserved cone PRs. Longitudinal assessment via optical coherence tomography (OCT) and electroretinography (ERG) revealed sustained structural and functional protection in NAC-treated mice. These findings establish oxidative DNA damage as a key driver of PR degeneration in the\n                  <jats:italic>Nmnat1<\/jats:italic>\n                  <jats:sup>V9M\/V9M<\/jats:sup>\n                  model and highlight NAC\u2019s potential as a causal gene variant-independent therapeutic strategy for\n                  <jats:italic>NMNAT1<\/jats:italic>\n                  -associated IRD and potentially other IRDs in which oxidative DNA damage contributes to disease pathogenesis.\n                <\/jats:p>","DOI":"10.1101\/2025.06.05.658162","type":"posted-content","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T07:40:14Z","timestamp":1749195614000},"source":"Crossref","is-referenced-by-count":0,"title":["Oxidative DNA Damage Drives Apoptotic Photoreceptor Loss in\n                  <i>NMNAT1<\/i>\n                  -Associated Inherited Retinal Degeneration: A Therapeutic Opportunity"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9386-0071","authenticated-orcid":false,"given":"Hanmeng","family":"Zhang","sequence":"first","affiliation":[{"name":"Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Valestil","sequence":"additional","affiliation":[{"name":"Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A.","family":"Pierce","sequence":"additional","affiliation":[{"name":"Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, 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