Investigative ophthalmology & visual science · 2026
WDR34 Deficiency Disrupts Retrograde Intraflagellar Transport and Induces Unfolded Protein Response-Driven Inflammation and Retinal Degeneration.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Jia Bo, Xie Jianan, Zhou Xuebin, Tong Wanqing, Li Dan, Fu Jinling
Аннотация
PURPOSE: Retinitis pigmentosa (RP) is a hereditary retinal disease characterized by progressive photoreceptor cell (PRC) degeneration. WD repeat domain 34 (WDR34), an intermediate chain of dynein-2, is essential for retrograde intraflagellar transport (IFT). However, the mechanisms by which WDR34 deficiency causes retinal degeneration remain unclear. This study aims to investigate the impact of WDR34 deficiency on retrograde IFT and its contribution to retinal degeneration.
METHODS: WDR34 deficiency was modeled in vivo via subretinal injection of adeno-associated virus-shRNA-WDR34 and in vitro by CRISPR/Cas9-mediated knockout in 661W cells. Retinal degeneration and IFT defects were assessed by histologic, functional, and ultrastructural analyses. Proteomic analysis followed by in vivo validation was used to investigate the molecular mechanism underlying WDR34-deficient retinal degeneration.
RESULTS: WDR34 knockdown induced progressive retinal degeneration characterized by PRC apoptosis, gradual outer nuclear layer thinning, reduced electroretinography responses, and outer segment shortening. WDR34 deficiency impaired retrograde IFT and caused rhodopsin and opsin mislocalization. These alterations induced endoplasmic reticulum stress and unfolded protein response (UPR) activation, activating the IRE1α/TRAF2/NF-κB signaling pathway, ultimately contributing to retinal inflammation and degeneration.
CONCLUSIONS: WDR34 is crucial for maintaining retrograde IFT in PRCs. WDR34 deficiency disrupts outer segment maintenance and triggers UPR-mediated inflammatory responses and apoptosis, ultimately leading to retinal degeneration. This study reveals a novel mechanistic link among WDR34, retrograde IFT, ciliopathies, and retinal degeneration, providing potential therapeutic insights for ciliopathy-associated RP.
METHODS: WDR34 deficiency was modeled in vivo via subretinal injection of adeno-associated virus-shRNA-WDR34 and in vitro by CRISPR/Cas9-mediated knockout in 661W cells. Retinal degeneration and IFT defects were assessed by histologic, functional, and ultrastructural analyses. Proteomic analysis followed by in vivo validation was used to investigate the molecular mechanism underlying WDR34-deficient retinal degeneration.
RESULTS: WDR34 knockdown induced progressive retinal degeneration characterized by PRC apoptosis, gradual outer nuclear layer thinning, reduced electroretinography responses, and outer segment shortening. WDR34 deficiency impaired retrograde IFT and caused rhodopsin and opsin mislocalization. These alterations induced endoplasmic reticulum stress and unfolded protein response (UPR) activation, activating the IRE1α/TRAF2/NF-κB signaling pathway, ultimately contributing to retinal inflammation and degeneration.
CONCLUSIONS: WDR34 is crucial for maintaining retrograde IFT in PRCs. WDR34 deficiency disrupts outer segment maintenance and triggers UPR-mediated inflammatory responses and apoptosis, ultimately leading to retinal degeneration. This study reveals a novel mechanistic link among WDR34, retrograde IFT, ciliopathies, and retinal degeneration, providing potential therapeutic insights for ciliopathy-associated RP.