title: ERK1/2 activation is a therapeutic target in age-related macular degeneration.
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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Sami
authors.initials: S
authors.lastname: Dridi
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hirano
authors.forename: Valeria
authors.initials: V
authors.lastname: Tarallo
authors.forename: Younghee
authors.initials: Y
authors.lastname: Kim
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Fowler
authors.forename: Balamurali K
authors.initials: BK
authors.lastname: Ambati
authors.forename: Sasha
authors.initials: S
authors.lastname: Bogdanovich
authors.forename: Vince A
authors.initials: VA
authors.lastname: Chiodo
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Kugel
authors.forename: James A
authors.initials: JA
authors.lastname: Goodrich
authors.forename: Steven L
authors.initials: SL
authors.lastname: Ponicsan
authors.forename: David R
authors.initials: DR
authors.lastname: Hinton
authors.forename: Mark E
authors.initials: ME
authors.lastname: Kleinman
authors.forename: Judit Z
authors.initials: JZ
authors.lastname: Baffi
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Gelfand
authors.forename: Jayakrishna
authors.initials: J
authors.lastname: Ambati
mesh_terms: D000818:Animals; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008268:Macular Degeneration / Q000201:enzymology* / Q000628:therapy*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D055213:Retinal Pigment Epithelium / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C408087:DICER1 protein, human; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one