Functional compartmentalization of photoreceptor neurons

Malhotra, Himanshu; Barnes, Cassandra; Calvert, Peter D.

doi:10.1007/s00424-021-02558-7

Cited by 12 publications

(3 citation statements)

References 280 publications

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“…Photosensitive proteins are synthesized in the inner segment and the region adjacent to the cell body. The inner segment is enriched with rough endoplasmic reticulum, mitochondria, and the Golgi complex [ 17 ]. In db/db mouse retinas, the outer layer of photoreceptors exhibited swelling with mitochondrial hypertrophy, and the Golgi vesicles were visibly dilated and blurry compared to db/m mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

WNT-inhibitory factor 1-mediated glycolysis protects photoreceptor cells in diabetic retinopathy

Chen,

Zou,

Xie

et al. 2024

J Transl Med

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Background In diabetic retinopathy (DR), hypoxia-inducible factor (HIF-1α) induces oxidative stress by upregulating glycolysis. This process leads to neurodegeneration, particularly photoreceptor cell damage, which further contributes to retinal microvascular deterioration. Further, the regulation of Wnt-inhibitory factor 1 (WIF1), a secreted Wnt signaling antagonist, has not been fully characterized in neurodegenerative eye diseases. We aimed to explore the impact of WIF1 on photoreceptor function within the context of DR. Method Twelve-week-old C57BL/KsJ-db/db mice were intravitreally injected with WIF1 overexpression lentivirus. After 4 weeks, optical coherence tomography (OCT), transmission electron microscopy (TEM), H&E staining, and electroretinography (ERG) were used to assess the retinal tissue and function. The potential mechanism of action of WIF1 in photoreceptor cells was explored using single-cell RNA sequencing. Under high-glucose conditions, 661 W cells were used as an in vitro DR model. WIF1-mediated signaling pathway components were assessed using quantitative real-time PCR, immunostaining, and western blotting. Result Typical diabetic manifestations were observed in db/db mice. Notably, the expression of WIF1 was decreased at the mRNA and protein levels. These pathological manifestations and visual function improved after WIF1 overexpression in db/db mice. TEM demonstrated that WIF1 restored damaged mitochondria, the Golgi apparatus, and photoreceptor outer segments. Moreover, ERG indicated the recovery of a-wave potential amplitude. Single-cell RNA sequencing and in vitro experiments suggested that WIF1 overexpression prevented the expression of glycolytic enzymes and lactate production by inhibiting the canonical Wnt signaling pathway, HIF-1α, and Glut1, thereby reducing retinal and cellular reactive oxygen species levels and maintaining 661 W cell viability. Conclusions WIF1 exerts an inhibitory effect on the Wnt/β-catenin-HIF-1α-Glut1 glycolytic pathway, thereby alleviating oxidative stress levels and mitigating pathological structural characteristics in retinal photoreceptor cells. This mechanism helps preserve the function of photoreceptor cells in DR and indicates that WIF1 holds promise as a potential therapeutic candidate for DR and other neurodegenerative ocular disorders. Graphical Abstract

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Section: Resultsmentioning

confidence: 99%

WNT-inhibitory factor 1-mediated glycolysis protects photoreceptor cells in diabetic retinopathy

Chen,

Zou,

Xie

et al. 2024

J Transl Med

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“…Retinal photoreceptors convert light into electrical signals in the first step of vision (reviewed in ( 1 , 2 )). Light transduction depends on opsin proteins ( Fig.…”

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confidence: 99%

“…Light transduction depends on opsin proteins ( Fig. 1 A ), canonical seven transmembrane domain G protein–coupled receptors (GPCRs), to be localized at high density within disc membranes of the photoreceptor ciliary outer segment, reaching 3 mM concentration relative to the outer segment plasma membrane envelope ( 1 , 2 ). The outer segments undergo 3 to 10% daily turnover (depending on species), thus the delivery rate of opsins to this ciliary compartment is exceptionally high.…”

mentioning

confidence: 99%