Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration
Open accessAbstract
Significance: Alu elements, comprising more than 10% of the human genome, propagate via retrotransposition. This genomic expansion requires enzymatic activity of L1 that reverse transcribes Alu RNA into Alu cDNA in the nucleus. We report Alu also undergoes L1-mediated reverse transcription via self-priming in the cytoplasm independent of retrotransposition, providing evidence of human DNA synthesis in this cellular compartment. This newly discovered shunt molecule in the Alu replication cycle also induces death of the retinal pigmented epithelium, a hallmark of atrophic age-related macular degeneration. A Big Data Archeology analysis of multiple health insurance databases reveals that use of FDA-approved nucleoside reverse transcriptase inhibitors is associated with protection against macular degeneration, identifying a repurposing candidate for this blinding disease.
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Alu RNA was reverse transcribed in the cytoplasm and the cDNA activated cGAS/STING signaling.
“Alu RNA was reverse transcribed in the cytoplasm and the cDNA activated cGAS/STING signaling95.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [95]
The Results (p. 3) report that Alu cDNA accumulates predominantly in the cytoplasm and requires reverse-transcriptase activity. The Discussion (page not provided) places Alu cDNA synthesis upstream of inflammasome activation, but our copy does not say that the cDNA activates cGAS/STING signaling. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe ensuing IFN-I and inflammatory responses in AMD were mitigated by treatment with NRTIs.
“The ensuing IFN-I and inflammatory responses were mitigated by treatment with NRTIs95, 129.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [95]
The Results section describes anti-inflammatory effects of NRTIs, and the Discussion says they can inhibit inflammasome activation and protect against Alu RNA-induced retinal degeneration. The human AMD analysis finds an association between NRTI use and lower atrophic AMD risk. However, our copy does not report that NRTI treatment mitigated IFN-I responses in AMD; searches for IFN and interferon found no supporting passage. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAlu self-priming in the cytoplasm has recently been reported in age-related macular degeneration.
“Alu self-priming in the cytoplasm has recently been reported in age-related macular degeneration (AMD)95.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [95]
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- Authors
- Fukuda, S., Varshney, A., Fowler, B. J., Wang, S.-B., Narendran, S., Ambati, K., Yasuma, T., Magagnoli, J., Leung, H., Hirahara, S., Nagasaka, Y., Yasuma, R., Apicella, I., Pereira, F., Makin, R. D., Magner, E., Liu, X., Sun, J., Wang, M., Baker, K., Marion, K. M., Huang, X., Baghdasaryan, E., Ambati, M., Ambati, V. L., Pandey, A., Pandya, L., Cummings, T., Banerjee, D., Huang, P., Yerramothu, P., Tolstonog, G. V., Held, U., Erwin, J. A., Paquola, A. C. M., Herdy, J. R., Ogura, Y., Terasaki, H., Oshika, T., Darwish, S., Singh, R. K., Mozaffari, S., Bhattarai, D., Kim, K. B., Hardin, J. W., Bennett, C. L., Hinton, D. R., Hanson, T. E., Röver, C., Parang, K., Kerur, N., Liu, J., Werner, B. C., Sutton, S. S., Sadda, S. R., Schumann, G. G., Gelfand, B. D., Gage, F. H., & Ambati, J.
- Affiliations
- University of Tsukuba (JP)
- University of Virginia (US)
- University of Kentucky (US)
- Aravind Eye Hospital (IN)
- University of South Carolina (US)
- Nagoya City University (JP)
- Doheny Eye Institute (US)
- University of California, Los Angeles (US)
- Center for Digital Image Evaluation (US)
- Centre Hospitalier Universitaire Vaudois (CH)
- Paul Ehrlich Institut (DE)
- Johns Hopkins University (US)
- The Lieber Institute for Brain Development, School of Medicine, Johns Hopkins University, Baltimore, MD 21205;
- Salk Institute for Biological Studies (US)
- Nagoya University (JP)
- Chapman University (US)
- University of Southern California (US)
- University of Minnesota (US)
- Universitätsmedizin Göttingen (DE)
- Corresponding author
- Fukuda, Shinichi
- Varshney, Akhil
- Gage, Fred H.
- Ambati, Jayakrishna
- ORCID
- Varshney, Akhil
- Fowler, Benjamin J.
- Wang, Shao-bin
- Narendran, Siddharth
- Yasuma, Tetsuhiro
- Magagnoli, Joseph
- Nagasaka, Yosuke
- Yasuma, Reo
- Apicella, Ivana
- Pereira, Felipe
- Makin, Ryan D.
- Liu, Xinan
- Sun, Jian
- Wang, Mo
- Baker, Kirstie
- Marion, Kenneth M.
- Huang, Xiwen
- Baghdasaryan, Elmira
- Ambati, Meenakshi
- Ambati, Vidya L.
- Pandey, Akshat
- Cummings, Tammy
- Banerjee, Daipayan
- Huang, Peirong
- Yerramothu, Praveen
- Tolstonog, Genrich V.
- Held, Ulrike
- Erwin, Jennifer A.
- Herdy, Joseph R.
- Ogura, Yuichiro
- Terasaki, Hiroko
- Oshika, Tetsuro
- Darwish, Shaban
- Singh, Ramendra K.
- Kim, Kyung Bo
- Hardin, James W.
- Bennett, Charles L.
- Hinton, David R.
- Hanson, Timothy E.
- Röver, Christian
- Parang, Keykavous
- Kerur, Nagaraj
- Liu, Jinze
- Sutton, S. Scott
- Sadda, Srinivas R.
- Schumann, Gerald G.
- Gelfand, Bradley D.
- Gage, Fred H.
- Ambati, Jayakrishna
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2021-02
- Volume
- 118
- Issue
- 6
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC8017980
- OpenAlex
- W3128986733
- Cited by
- 65
- References
- 59
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 10 · 2023: 13 · 2022: 10 · 2021: 11
- FWCI
- 6.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- NIH (DP1GM114862, R01EY022238, R01EY024068, R01EY028027, R01EY29799, R01EY031039, K99EY024336, R00EY024336, T32HL091812, UL1RR033173, R01EY001545, R01EY031039), UL1TR000117)
- NH (R21EY030651)
- Federal Republic of Germany (FKZ2518FSB403)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- Alu elements, LINE-1 retrotransposons, age-related macular degeneration, nucleoside reverse transcriptase inhibitors, drug repurposing
- MeSH terms
- Animals, Cytoplasm, Epithelium, Humans, Macular Degeneration, Retinal Pigments, DNA, Complementary, Retroelements, Long Interspersed Nucleotide Elements, Alu Elements, Reverse Transcription
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