Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 6, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2022751118
Keywords
Alu; retrotransposon; macular degeneration; retina; health insurance databases
Categories
Funding
- NIH [DP1GM114862, R01EY022238, R01EY024068, R01EY028027, R01EY29799, R01EY031039, K99EY024336, R00EY024336, R21EY030651, T32HL091812, UL1RR033173, R01EY001545]
- DuPont Guerry III Professorship
- University of Virginia Strategic Investment Fund
- John Templeton Foundation [60763]
- Doris Duke Distinguished Clinical Scientist Award
- Ellison Medical Foundation Senior Scholar in Aging Award
- Dr. E. Vernon Smith and Eloise C. SmithMacular Degeneration Endowed Chair
- Japan Society for the Promotion of Science Fund for the Promotion of Joint International Research (Home-Returning Researcher Development Research)
- Japan Eye Bank Association
- Beckman Initiative for Macular Research
- Association for Research in Vision and Ophthalmology/Alcon Early Career Clinician-Scientist Research Award
- Fight for Sight postdoctoral award
- Fulbright Visiting Scholar Program
- Research to Prevent Blindness
- BrightFocus Foundation
- Owens Family Foundation
- American Heart Association
- National Center for Research Resources
- National Center for Advancing Translational Sciences, NIH [UL1TR000117]
- Ministry of Health of the Federal Republic of Germany [FKZ2518FSB403]
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Alu retrotransposons propagate through reverse transcription using L1 elements, with cytoplasmic Alu cDNA inducing retinal pigmented epithelium degeneration independently of integration. Inhibitors of this process may be potential therapies for atrophic macular degeneration.
Alu retroelements propagate via retrotransposition by hijacking long interspersed nuclear element-1 (L1) reverse transcriptase (RT) and endonuclease activities. Reverse transcription of Alu RNA into complementary DNA (cDNA) is presumed to occur exclusively in the nucleus at the genomic integration site. Whether Alu cDNA is synthesized independently of genomic integration is unknown. Alu RNA promotes retinal pigmented epithelium (RPE) death in geographic atrophy, an untreatable type of age-related macular degeneration. We report that Alu RNA-induced RPE degeneration is mediated via cytoplasmic L1-reverse-transcribed Alu cDNA independently of retrotransposition. Alu RNA did not induce cDNA production or RPE degeneration in L1-inhibited animals or human cells. Alu reverse transcription can be initiated in the cytoplasm via self-priming of Alu RNA. In four health insurance databases, use of nucleoside RT inhibitors was associated with reduced risk of developing atrophic macular degeneration (pooled adjusted hazard ratio, 0.616; 95% confidence interval, 0.493-0.770), thus identifying inhibitors of this Alu replication cycle shunt as potential therapies for a major cause of blindness.
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