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Sortilin participates in light-dependent photoreceptor degeneration in vivo.

ABSTRACT: Both proNGF and the neurotrophin receptor p75 (p75(NTR)) are known to regulate photoreceptor cell death caused by exposure of albino mice to intense illumination. ProNGF-induced apoptosis requires the participation of sortilin as a necessary p75(NTR) co-receptor, suggesting that sortilin may participate in the photoreceptor degeneration triggered by intense lighting. We report here that light-exposed albino mice showed sortilin, p75(NTR), and proNGF expression in the outer nuclear layer, the retinal layer where photoreceptor cell bodies are located. In addition, cone progenitor-derived 661W cells subjected to intense illumination expressed sortilin and p75(NTR) and released proNGF into the culture medium. Pharmacological blockade of sortilin with either neurotensin or the "pro" domain of proNGF (pro-peptide) favored the survival of 661W cells subjected to intense light. In vivo, the pro-peptide attenuated retinal cell death in light-exposed albino mice. We propose that an auto/paracrine proapoptotic mechanism based on the interaction of proNGF with the receptor complex p75(NTR)/sortilin participates in intense light-dependent photoreceptor cell death. We therefore propose sortilin as a putative target for intervention in hereditary retinal dystrophies.

SUBMITTER: Santos AM

PROVIDER: S-EPMC3338683 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Sortilin participates in light-dependent photoreceptor degeneration in vivo.

Santos Ana M AM López-Sánchez Noelia N Martín-Oliva David D de la Villa Pedro P Cuadros Miguel A MA Frade José M JM

PloS one 20120427 4

Both proNGF and the neurotrophin receptor p75 (p75(NTR)) are known to regulate photoreceptor cell death caused by exposure of albino mice to intense illumination. ProNGF-induced apoptosis requires the participation of sortilin as a necessary p75(NTR) co-receptor, suggesting that sortilin may participate in the photoreceptor degeneration triggered by intense lighting. We report here that light-exposed albino mice showed sortilin, p75(NTR), and proNGF expression in the outer nuclear layer, the ret ...[more]

PMID: 22558402

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Project description:Oxidative stress and inflammation play key roles in the light damage (LD) model of photoreceptor degeneration, as well as in age-related macular degeneration (AMD). We sought to investigate whether Berberine (BBR), an antioxidant herb extract, would protect the retina against light-induced degeneration. To accomplish this, Balb/c mice were treated with BBR or PBS via gavage for 7 days, and then were placed in constant cool white light-emitting diode (LED) light (10,000 lux) for 4 h. Retinal function and degeneration were evaluated by histology, electroretinography (ERG) and optical coherence tomography (OCT) at 7d after LD. Additionally, mRNA levels of cell-type specific, antioxidant, and inflammatory genes were compared 7d after LD. Photoreceptor DNA fragmentation was assessed via the terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assay. LD resulted in substantial photoreceptor-specific cell death. Histological analysis using plastic sections showed dosing with BBR preserved photoreceptors. The ERG analysis demonstrated functional protection by BBR in rod-b, -a, and cone-b waves. In OCT images, mice receiving PBS showed severe thinning and disorganization of the photoreceptor layer 7 days after LD, whereas mice treated with BBR had significantly less thinning and disorganization. Consistent with OCT results, the mRNA levels of Rho in the NSR, and Rpe65 and Mct3 in the RPE, were significantly higher in mice treated with BBR. The numbers of TUNEL-positive photoreceptors were significantly decreased in BBR-treated mice. The retinal mRNA levels of oxidative stress genes, the number of microglia/macrophages, and the malondialdehyde (MDA) immunolabeling were significantly lower in BBR-treated mice compared to controls 48 h after LD, which indicates oxidative stress was reduced by BBR in light-damaged eyes. In conclusion, systemic BBR is protective against light-induced retinal degeneration associated with diminished oxidative stress in the retina. These results suggest that BBR may be protective against retinal diseases involving oxidative stress.

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Sortilin participates in light-dependent photoreceptor degeneration in vivo.

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Sortilin participates in light-dependent photoreceptor degeneration in vivo.

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