TY - JOUR
T1 - DICER1/Alu RNA dysmetabolism induces caspase-8-mediated cell death in age-related macular degeneration
AU - Kim, Younghee
AU - Tarallo, Valeria
AU - Kerur, Nagaraj
AU - Yasuma, Tetsuhiro
AU - Gelfand, Bradley D.
AU - Bastos-Carvalho, Ana
AU - Hirano, Yoshio
AU - Yasuma, Reo
AU - Mizutani, Takeshi
AU - Fowler, Benjamin J.
AU - Li, Shengjian
AU - Kaneko, Hiroki
AU - Bogdanovich, Sasha
AU - Ambatif, Balamurali K.
AU - Hinton, David R.
AU - Hauswirth, William W.
AU - Hakem, Razqallah
AU - Wright, Charles
AU - Ambati, Jayakrishna
PY - 2014/11/11
Y1 - 2014/11/11
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84909609625&partnerID=8YFLogxK
U2 - 10.1073/pnas.1403814111
DO - 10.1073/pnas.1403814111
M3 - Article
C2 - 25349431
AN - SCOPUS:84909609625
SN - 0027-8424
VL - 111
SP - 1682
EP - 1687
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 45
ER -
