Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration
Shinichi Fukuda,Shinichi Fukuda,Akhil Varshney,Benjamin J. Fowler,Shaobin Wang,Siddharth Narendran,Siddharth Narendran,Kameshwari Ambati,Tetsuhiro Yasuma,Tetsuhiro Yasuma,Joseph Magagnoli,Joseph Magagnoli,Hannah Leung,Shuichiro Hirahara,Shuichiro Hirahara,Yosuke Nagasaka,Reo Yasuma,Reo Yasuma,Ivana Apicella,Felipe Pereira,Felipe Pereira,Ryan D. Makin,Eamonn Magner,Xinan Liu,Jian Sun,Mo Wang,Kirstie Baker,Kenneth M. Marion,Xiwen Huang,Elmira Baghdasaryan,Meenakshi Ambati,Vidya L. Ambati,Akshat Pandey,Lekha Pandya,Tammy H. Cummings,Tammy H. Cummings,Daipayan Banerjee,Peirong Huang,Praveen Yerramothu,Genrich V. Tolstonog,Ulrike Held,Jennifer A. Erwin,Apuã C. M. Paquola,Joseph R. Herdy,Yuichiro Ogura,Hiroko Terasaki,Tetsuro Oshika,Shaban Darwish,Ramendra K. Singh,Saghar Mozaffari,Deepak Bhattarai,Kyung Bo Kim,James W. Hardin,James W. Hardin,Charles L. Bennett,Charles L. Bennett,David R. Hinton,Timothy Hanson,Timothy Hanson,Christian Röver,Keykavous Parang,Nagaraj Kerur,Jinze Liu,Brian C. Werner,S Scott Sutton,S Scott Sutton,Srinivas R. Sadda,Gerald G. Schumann,Bradley D. Gelfand,Fred H. Gage,Jayakrishna Ambati +70 more
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TLDR
In this article, the authors reported that Alu RNA-induced RPE degeneration is mediated via cytoplasmic L1-reverse-transcribed Alu cDNA independently of retrotransposition.Abstract:
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.read more
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The role of retrotransposable elements in ageing and age-associated diseases
Vera Gorbunova,Andrei Seluanov,Paolo Mita,Wilson McKerrow,David Fenyö,Jef D. Boeke,Sara B. Linker,Fred H. Gage,Jill A. Kreiling,Anna P. Petrashen,Trenton A. Woodham,Jackson Taylor,Stephen L. Helfand,John M. Sedivy +13 more
TL;DR: In this paper, the authors discuss new evidence and ideas that the activity of retrotransposons, a major subgroup of transposons overall, influences and even promotes the process of ageing and age-related diseases in complex metazoan organisms, including humans.
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Cytoplasmic DNA: sources, sensing, and role in aging and disease.
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Identification of fluoxetine as a direct NLRP3 inhibitor to treat atrophic macular degeneration.
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TL;DR: In this paper, fluoxetine, an FDA-approved drug for treating clinical depression, binds NLRP3 in silico, in vitro, and in vivo and inhibits activation of the NLRP 3-ASC inflammasome and inflammatory cytokine release in RPE cells and macrophages, two critical cell types in dry AMD.
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