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

Younghee Kim, Valeria Tarallo, Nagaraj Kerur, Tetsuhiro Yasuma, Bradley D. Gelfand, Ana Bastos-Carvalho, Yoshio Hirano, Reo Yasuma, Takeshi Mizutani, Benjamin J. Fowler, Shengjian Li, Hiroki Kaneko, Sasha Bogdanovich, Balamurali K. Ambatif, David R. Hinton, William W. Hauswirth, Razqallah Hakem, Charles Wright, Jayakrishna Ambati*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1682-1687
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number45
DOIs
StatePublished - Nov 11 2014

ASJC Scopus subject areas

  • General

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