Abstract
Retinal degeneration (RD) is an intractable ophthalmic disorder with no effective treatments, and its pathogenesis is complex, involving multiple genes. Endoplasmic reticulum (ER) stress and neuronal apoptosis are key factors that drive neurodegeneration in retinal degeneration. B cell receptor-associated protein 31 (BAP31) is a transmembrane protein predominantly found in the ER, which plays an important role in regulating ER stress and apoptosis. To date, no studies have directly confirmed the association between BAP31 and retinal degenerative diseases. However, considering that ER dysfunction is a key trigger for retinal photoreceptor cell damage and that BAP31 acts as a core regulator of ER function, we hypothesize that BAP31 may be involved in the development of retinal degeneration by regulating ER homeostasis. Our study aimed to investigate the pathogenic mechanisms of BAP31 in retinal disorders. A rod-specific conditional knockdown of BAP31 mouse model (Rho-iCre-BAP31fl/fl(-/-)) was employed to explore the role of BAP31 in retinal pathogenesis. The Rho-iCre-BAP31fl/fl(-/-) mice exhibited phenotypes similar to retinitis pigmentosa (RP), including decreased ERG responses, photoreceptor degeneration, and reduced visual function. Optical coherence tomography (OCT) results showed that the outer nuclear layer (ONL) of the retina in conditional knockdown mice exhibited progressive thinning after 9 months of age; histopathological examination results were consistent with those of OCT. These findings indicated that the rod photoreceptor cells in the conditional knockdown mice showed damage and irregular arrangement starting at 9 months of age, with more prominent changes by 12 months. RNA sequence analysis of 12-month-old mice indicated enrichment of the phototransduction pathway, with significant downregulation of key genes (rhodopsin, recoverin, Gnat1, Pde6a, and Pde6b) involved in retinal development and phototransduction, along with a marked increase in Gfap expression (indicating glial activation and retinal damage). Quantitative real-time PCR and Western blot analyses showed significant upregulation of unfolded protein response (UPR) marker proteins (BIP, CHOP, XBP1, ATF4, ATF6), demonstrating robust ER stress activation. The findings suggest that BAP31 deficiency induces retinal degeneration, and the activation of the ER stress may contribute to the pathogenic mechanisms underlying this process.