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Thus, we undertook to unlock features of the P23H\/+ knock-in mouse model. Bisretinoids, the source of short-wavelength fundus autofluorescence (SW-AF), were elevated in albino P23H rhodopsin transgenic rats and in black and albino P23H\/+ mice relative to wild type. Conversely, bisretinoid levels were lower in albino P23H\/+ relative to black P23H\/+ mice. Fluorescence microscopy revealed an inherent and aberrant autofluorescence in photoreceptor inner segments of albino P23H\/+ mice. Outer nuclear layer (ONL) thinning indicative of photoreceptor degeneration was more pronounced in albino versus black P23H\/+ mice and was accentuated in inferior versus superior hemiretina. Dark-rearing alleviated ONL thinning in albino P23H\/+. The greatly diminished levels of ocular retinoid were not fully accounted for by loss of photoreceptor cells. P23H\/+ mice treated with the antioxidant N-acetylcysteine (NAC) exhibited higher intensities of SW-AF, improved photoreceptor viability, and diminished 4-hydroxynonenal (HNE) immunoreactivity; the latter included 4-HNE adducts deposited in association with photoreceptor cells. The lower levels of bisretinoid in association with higher retinal illuminance are indicative of toxic bisretinoid photooxidation\/degradation while the higher bisretinoid levels conferred by NAC are consistent with inhibition of these photodegradative processes. Collectively, these findings reveal that anomalous bisretinoid production can account for fundus hyperautofluorescence, and the photoreactive properties of bisretinoids can explain the propensity for environmental light to exacerbate photoreceptor cell degeneration. The findings support the benefits of antioxidant intervention in human adRP.<\/jats:p>","DOI":"10.1093\/pnasnexus\/pgag088","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T17:35:50Z","timestamp":1775064950000},"source":"Crossref","is-referenced-by-count":0,"title":["Disease mechanisms revealed in the P23H opsin knock-in mouse model of retinitis pigmentosa"],"prefix":"10.1093","volume":"5","author":[{"given":"Jin","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Columbia University Medical Center , New York, NY 10032 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6892-7492","authenticated-orcid":false,"given":"Diego","family":"Montenegro","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Columbia University Medical Center , New York, NY 10032 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7363-4053","authenticated-orcid":false,"given":"Hye Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Columbia University Medical Center , New York, NY 10032 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keiko","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Columbia University Medical Center , New York, NY 10032 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7448-5950","authenticated-orcid":false,"given":"Janet R","family":"Sparrow","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Columbia University Medical Center , New York, NY 10032 ,","place":["USA"]},{"name":"Department of Pathology and Cell Biology, Columbia University Medical Center , New York, NY 10032 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"key":"2026041702414683900_pgag088-B1","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1016\/S0140-6736(06)69740-7","article-title":"Retinitis pigmentosa","volume":"368","author":"Hartong","year":"2006","journal-title":"Lancet"},{"key":"2026041702414683900_pgag088-B2","first-page":"1659","article-title":"Retinitis pigmentosa. 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