April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Alu RNA Induced Rpe Cell Apoptosis Triggered By DICER Dysregulation In Geographic Atrophy
Author Affiliations & Notes
  • Valeria Tarallo
    Ophthalmology, University of Kentucky, Lexington, Kentucky
  • Sami Dridi
    Ophthalmology, University of Kentucky, Lexington, Kentucky
  • Hiroki Kaneko
    Ophthalmology, University of Kentucky, Lexington, Kentucky
  • Mark E. Kleinman
    Ophthalmology, University of Kentucky, Lexington, Kentucky
  • Benjamin J. Fowler
    Ophthalmology, University of Kentucky, Lexington, Kentucky
  • Romulo J. Albuquerque
    Ophthalmology, University of Kentucky, Lexington, Kentucky
  • Judit Z. Baffi
    Ophthalmology, University of Kentucky, Lexington, Kentucky
  • Jayakrishna Ambati
    Ophthalmology, University of Kentucky, Lexington, Kentucky
  • Footnotes
    Commercial Relationships  Valeria Tarallo, None; Sami Dridi, None; Hiroki Kaneko, None; Mark E. Kleinman, None; Benjamin J. Fowler, None; Romulo J. Albuquerque, None; Judit Z. Baffi, None; Jayakrishna Ambati, Allergan (C), Genentech (C)
  • Footnotes
    Support  NIH/NEI, Doris Duke Charitable Foundation, Burroughs Wellcome Fund, RPB
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 2314. doi:https://doi.org/
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      Valeria Tarallo, Sami Dridi, Hiroki Kaneko, Mark E. Kleinman, Benjamin J. Fowler, Romulo J. Albuquerque, Judit Z. Baffi, Jayakrishna Ambati; Alu RNA Induced Rpe Cell Apoptosis Triggered By DICER Dysregulation In Geographic Atrophy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2314. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract
 
Purpose:
 

Geographic atrophy (GA), an advanced form of age-related macular degeneration that causes blindness in millions of people worldwide, results from death of retinal pigmented epithelium (RPE) cells. We recently identified that human eyes with GA exhibit reduced levels of DICER and accumulation of cytotoxic Alu repeat RNAs. We sought to determine the relationship between these observations in the context of RPE cell viability.

 
Methods:
 

The effect of DICER knockdown (by antisense or Cre/LoxP ablation) on Alu RNA accumulation and on cell viability was assayed. The ability of DICER to degrade Alu was studied. The administration of Alu RNA on cell viability was assayed in human and in mouse RPE.

 
Results:
 

DICER knockdown in human RPE induces accumulation of Alu RNA and cell death over time. Similarly, Ad-Cre infection of RPE cells isolated from Dicerf/f mice results in accumulation of B1 and B2 (Alu-like elements) repeat RNAs. Recombinant DICER degrades Alu RNA, and overexpression of DICER prevents accumulation of Alu RNA induced by DICER knockdown in human RPE cells. Alu RNA administration induces human RPE cell cytotoxicity via caspase-3 activation, and DICER overexpression protects RPE cells from Alu RNA-induced cytotoxicity. Human or mouse RPE cell death triggered by DICER knockdown is inhibited by antisense oligonucleotides targeting Alu/B1/B2 RNA.

 
Conclusions:
 

These data reveal a novel cell survival function of DICER mediated via its degradation of retrotransposon transcripts and introduce the concept that Alu can cause human pathology via direct RNA toxicity.

 
Keywords: age-related macular degeneration • apoptosis/cell death • signal transduction 
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