title: 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.
authors.affiliation: Department of Ophthalmology and Visual Sciences.
authors.forename: Younghee
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Ophthalmology and Visual Sciences, Angiogenesis Lab, Institute of Genetics and Biophysics, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy;
authors.forename: Valeria
authors.initials: V
authors.lastname: Tarallo
authors.affiliation: Department of Ophthalmology and Visual Sciences.
authors.forename: Nagaraj
authors.initials: N
authors.lastname: Kerur
authors.affiliation: Department of Ophthalmology and Visual Sciences.
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Yasuma
authors.affiliation: Department of Ophthalmology and Visual Sciences, Department of Biomedical Engineering, Department of Microbiology, Immunology, and Human Genetics, and.
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Gelfand
authors.affiliation: Department of Ophthalmology and Visual Sciences.
authors.forename: Ana
authors.initials: A
authors.lastname: Bastos-Carvalho
authors.affiliation: Department of Ophthalmology and Visual Sciences.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hirano
authors.affiliation: Department of Ophthalmology and Visual Sciences.
authors.forename: Reo
authors.initials: R
authors.lastname: Yasuma
authors.affiliation: Department of Ophthalmology and Visual Sciences.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mizutani
authors.affiliation: Department of Ophthalmology and Visual Sciences, Department of Physiology, University of Kentucky, Lexington, KY 40536;
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Fowler
authors.affiliation: Department of Ophthalmology and Visual Sciences.
authors.forename: Shengjian
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Ophthalmology and Visual Sciences.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kaneko
authors.affiliation: Department of Ophthalmology and Visual Sciences.
authors.forename: Sasha
authors.initials: S
authors.lastname: Bogdanovich
authors.affiliation: Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT 84132; Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, UT 84148;
authors.forename: Balamurali K
authors.initials: BK
authors.lastname: Ambati
authors.affiliation: Departments of Pathology and Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033;
authors.forename: David R
authors.initials: DR
authors.lastname: Hinton
authors.affiliation: Department of Ophthalmology, University of Florida, Gainesville, FL 32610; and.
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.affiliation: Ontario Cancer Institute, University Health Network, and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 2M9.
authors.forename: Razqallah
authors.initials: R
authors.lastname: Hakem
authors.affiliation: Department of Ophthalmology and Visual Sciences.
authors.forename: Charles
authors.initials: C
authors.lastname: Wright
authors.affiliation: Department of Ophthalmology and Visual Sciences, Department of Physiology, University of Kentucky, Lexington, KY 40536; jamba2@email.uky.edu.
authors.forename: Jayakrishna
authors.initials: J
authors.lastname: Ambati
mesh_terms: D020087:Alu Elements; D000818:Animals; D017209:Apoptosis; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D008268:Macular Degeneration / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D005136:Eye Proteins; D020382:Interleukin-18; D012313:RNA; C408087:DICER1 protein, human; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; D053181:Caspase 8; D053487:DEAD-box RNA Helicases
keywords: caspase; inflammasome; macular degeneration