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ERK1/2 activation is a therapeutic target in age-related macular degeneration.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2012 Aug 21; Vol. 109 (34), pp. 13781-6. Date of Electronic Publication: 2012 Aug 06. - Publication Year :
- 2012
-
Abstract
- 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.
- Subjects :
- Animals
DEAD-box RNA Helicases metabolism
Enzyme Activation
Enzyme Inhibitors pharmacology
Flavonoids pharmacology
Humans
Mice
Phosphorylation
Retinal Pigment Epithelium metabolism
Ribonuclease III metabolism
Signal Transduction
Gene Expression Regulation, Enzymologic
Macular Degeneration enzymology
Macular Degeneration therapy
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinase 3 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 109
- Issue :
- 34
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 22869729
- Full Text :
- https://doi.org/10.1073/pnas.1206494109