Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 34, Pages 13781-13786Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1206494109
Keywords
cell death; mobile elements; retinal degeneration
Categories
Funding
- National Eye Institute/National Institutes of Health (NIH) [R01EY018350, R01EY018836, R01EY020672, R01EY022238, R21EY019778, RC1EY020442]
- Doris Duke Distinguished Clinical Scientist Award
- Burroughs Wellcome Fund Clinical Scientist Award in Translational Research
- Dr. E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair
- Senior Scientist Investigator Award (Research to Prevent Blindness)
- NIH [K08EY021521, K08EY021757, T32HL091812, UL1RR033173, P30EY021721, R01EY017182, R01EY017950, P30EY003040, R01EY001545, R01GM068414]
- International Retinal Research Foundation
- American Health Assistance Foundation
- Alcon Japan Research Award
- Macula Vision Research Foundation
- Veterans Administration Merit Award
- Department of Defense
- Research to Prevent Blindness
- University of Kentucky Physician Scientist Awards
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Deficient expression of the RNase III DICER1, which leads to the accumulation of cytotoxic Alu RNA, has been implicated in degeneration of the retinal pigmented epithelium (RPE) in geographic atrophy (GA), a late stage of age-related macular degeneration that causes blindness in millions of people worldwide. Here we show increased extracellular-signal-regulated kinase (ERK) 1/2 phosphorylation in the RPE of human eyes with GA and that RPE degeneration in mouse eyes and in human cell culture induced by DICER1 depletion or Alu RNA exposure is mediated via ERK1/2 signaling. Alu RNA overexpression or DICER1 knockdown increases ERK1/2 phosphorylation in the RPE in mice and in human cell culture. Alu RNA-induced RPE degeneration in mice is rescued by intravitreous administration of PD98059, an inhibitor of the ERK1/2-activating kinase MEK1, but not by inhibitors of other MAP kinases such as p38 or JNK. These findings reveal a previously unrecognized function of ERK1/2 in the pathogenesis of GA and provide a mechanistic basis for evaluation of ERK1/2 inhibition in treatment of this disease.
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