Dataset Information

DICER1/Alu RNA dysmetabolism induces Caspase-8-mediated cell death in age-related macular degeneration.

ABSTRACT: Geographic atrophy, an advanced form of age-related macular degeneration (AMD) characterized by death of the retinal pigmented epithelium (RPE), causes untreatable blindness in millions worldwide. The RPE of human eyes with geographic atrophy accumulates toxic Alu RNA in response to a deficit in the enzyme DICER1, which in turn leads to activation of the NLRP3 inflammasome and elaboration of IL-18. Despite these recent insights, it is still unclear how RPE cells die during the course of the disease. In this study, we implicate the involvement of Caspase-8 as a critical mediator of RPE degeneration. Here we show that DICER1 deficiency, Alu RNA accumulation, and IL-18 up-regulation lead to RPE cell death via activation of Caspase-8 through a Fas ligand-dependent mechanism. Coupled with our observation of increased Caspase-8 expression in the RPE of human eyes with geographic atrophy, our findings provide a rationale for targeting this apoptotic pathway in this disease.

SUBMITTER: Kim Y

PROVIDER: S-EPMC4234570 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Publications

DICER1/Alu RNA dysmetabolism induces Caspase-8-mediated cell death in age-related macular degeneration.

Kim Younghee Y Tarallo Valeria V Kerur Nagaraj N Yasuma Tetsuhiro T Gelfand Bradley D BD Bastos-Carvalho Ana A Hirano Yoshio Y Yasuma Reo R Mizutani Takeshi T Fowler Benjamin J BJ Li Shengjian S Kaneko Hiroki H Bogdanovich Sasha S Ambati Balamurali K BK Hinton David R DR Hauswirth William W WW Hakem Razqallah R Wright Charles C Ambati Jayakrishna J

Proceedings of the National Academy of Sciences of the United States of America 20141027 45

Geographic atrophy, an advanced form of age-related macular degeneration (AMD) characterized by death of the retinal pigmented epithelium (RPE), causes untreatable blindness in millions worldwide. The RPE of human eyes with geographic atrophy accumulates toxic Alu RNA in response to a deficit in the enzyme DICER1, which in turn leads to activation of the NLRP3 inflammasome and elaboration of IL-18. Despite these recent insights, it is still unclear how RPE cells die during the course of the dise ...[more]

PMID: 25349431

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Project description:Non-exudative age-related macular degeneration, a prevalent cause of blindness, is a progressive and degenerative disease characterized by alterations in Bruch's membrane, retinal pigment epithelium, and photoreceptors exclusively localized in the macula. Although experimental murine models exist, the vast majority take a long time to develop retinal alterations and, in general, these alterations are ubiquitous, with many resulting from non-eye-specific genetic manipulations; additionally, most do not always reproduce the hallmarks of human age-related macular degeneration. Choroid vessels receive sympathetic innervation from the superior cervical ganglion, which, together with the parasympathetic system, regulates blood flow into the choroid. Choroid blood flow changes have been involved in age-related macular degeneration development and progression. At present, no experimental models take this factor into account. The aim of this work was to analyze the effect of superior cervical gangliectomy (also known as ganglionectomy) on the choroid, Bruch's membrane, retinal pigment epithelium and retina. Adult male C57BL/6J mice underwent unilateral superior cervical gangliectomy and a contralateral sham procedure. Although superior cervical gangliectomy induced ubiquitous choroid and choriocapillaris changes, it induced Bruch's membrane thickening, loss of retinal pigment epithelium melanin content and retinoid isomerohydrolase, the appearance of drusen-like deposits, and retinal pigment epithelium and photoreceptor atrophy, exclusively localized in the temporal side. Moreover, superior cervical gangliectomy provoked a localized increase in retinal pigment epithelium and photoreceptor apoptosis, and a decline in photoreceptor electroretinographic function. Therefore, superior cervical gangliectomy recapitulated the main features of human non-exudative age-related macular degeneration, and could become a new experimental model of dry age-related macular degeneration, and a useful platform for developing new therapies.

Dataset Information

DICER1/Alu RNA dysmetabolism induces Caspase-8-mediated cell death in age-related macular degeneration.

Publications

DICER1/Alu RNA dysmetabolism induces Caspase-8-mediated cell death in age-related macular degeneration.

Similar Datasets

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