Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration

  title={Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration},
  author={Shinichi Fukuda and Akhil Varshney and Benjamin J. Fowler and Shao-Bin Wang and Siddharth Narendran and Kameshwari Ambati and Tetsuhiro Yasuma and Joseph Magagnoli and Hannah Leung and Shuichiro Hirahara and Yosuke Nagasaka and Reo Yasuma and Ivana Apicella and Felipe Pereira and Ryan D. Makin and Eamonn Magner and Xinan Liu and Jian Sun and Mo Wang and Kirstie L. Baker and Kenneth M. Marion and Xiwen Huang and Elmira Baghdasaryan and Meenakshi Ambati and Vidya L. Ambati and Akshat Pandey and Lekha Pandya and Tammy H. Cummings and Daipayan Banerjee and Peirong Huang and Praveen Yerramothu and Genrich V Tolstonog and Ulrike Held and Jennifer A. Erwin and Apu{\~a} C. M. Paquola and Joseph R Herdy and Yuichiro Ogura and Hiroko Terasaki and Tetsuro Oshika and Shaban Darwish and Ramendra K. Singh and Saghar Mozaffari and Deepak Bhattarai and Kyung Bo Kim and James W. Hardin and Charles L Bennett and David R Hinton and Timothy E. Hanson and Christian R{\"o}ver and Keykavous Parang and Nagaraj Kerur and Jinze Liu and Brian C. Werner and S. Scott Sutton and Srinivas R. Sadda and Gerald G. Schumann and Bradley D. Gelfand and Fred H. Gage and Jayakrishna Ambati},
  journal={Proceedings of the National Academy of Sciences},
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… Expand
The role of retrotransposable elements in ageing and age-associated diseases.
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 are discussed. Expand
Sensing of transposable elements by the antiviral innate immune system.
A better biological understanding of the TE replicative cycle as well as of the antiviral nucleic acid sensing mechanisms will provide insights into how these two biological processes interact and will help to design better strategies to treat human diseases characterised by aberrant TE expression and/or type I IFN activation. Expand
Transposable elements as new players in neurodegenerative diseases
Transposable elements (TEs) might represent an overlooked pathogenic culprit for both brain aging and neurodegeneration and certain pathological effects of TEs might be prevented by inhibiting their activity, pointing to TEs as novel targets for neuroprotection. Expand
Cytoplasmic DNA: sources, sensing, and role in aging and disease
Current knowledge in this rapidly progressing field is summarized with emphases on similarities and differences between distinct cytoDNAs, their underlying molecular mechanisms of formation and function, interactions between cytoDNA pathways, and therapeutic opportunities in the treatment of age-associated diseases. Expand
Identification of fluoxetine as a direct NLRP3 inhibitor to treat atrophic macular degeneration
Fluoxetine, an FDA-approved drug for treating clinical depression, binds NLRP3 in silico, in vitro, and in vivo and inhibits activation of theNLRP3-ASC inflammasome and inflammatory cytokine release in RPE cells and macrophages, two critical cell types in dry AMD. Expand
High-Fat Diet Alters the Retinal Transcriptome in the Absence of Gut Microbiota
Novel data is demonstrated that diet can directly modulate the retinal transcriptome independently of the gut microbiome, and key genes involved in retinal inflammation, angiogenesis, and RPE function were identified. Expand
The learning curve of murine subretinal injection among clinically trained ophthalmic surgeons
This study demonstrates the complexity and substantial LC for successful SRI in mice with high confidence and shows a systematic training system could improve the reliability and reproducibility of SRI-related experiments and improve the interpretation of experimental results using this technique. Expand
Approved HIV reverse transcriptase inhibitors in the past decade
  • Guangdi Li, Yali Wang, E. De Clercq
  • Acta Pharmaceutica Sinica B
  • 2021


cGAS drives non-canonical inflammasome activation in age-related macular degeneration
It is demonstrated that RPE degeneration in human-cell-culture and mouse models is driven by a noncanonical-inflammasome pathway that activates caspase-4, gasdermin D, interferon-β, and cGAS levels were elevated in the RPE in human eyes with geographic atrophy, and an unexpected role of cGas in responding to mobile-element transcripts is highlighted. Expand
Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition
Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Expand
Structure of extrachromosomal circular DNAs containing both the Alu family of dispersed repetitive sequences and other regions of chromosomal DNA.
Small polydisperse circular DNA isolated from the BSC-1 line of African Green monkey kidney cells was digested with the restriction endonuclease BamHI and cloned in bacteriophage lambda, and four of the 100 Alu-positive clones were characterized. Expand
A Clinical Metabolite of Azidothymidine Inhibits Experimental Choroidal Neovascularization and Retinal Pigmented Epithelium Degeneration
GAZT possesses dual anti-inflammatory and anti-angiogenic properties and could be a viable treatment option for both forms of AMD. Expand
Repurposing anti-inflammasome NRTIs for improving insulin sensitivity and reducing type 2 diabetes development
It is shown that the adjusted risk of incident diabetes is 33% lower in patients with NRTI exposure among 128,861 patients with HIV-1 or hepatitis B, and the possibility of repurposing an approved class of drugs for prevention of diabetes is suggested. Expand
Peptide amphiphile containing arginine and fatty acyl chains as molecular transporters.
These studies suggest that PAs containing the appropriate sequence of amino acids, chain length, charge, and hydrophobicity can be used as cellular delivery tools for transporting drugs and biomolecules. Expand
Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis.
BACKGROUND Numerous population-based studies of age-related macular degeneration have been reported around the world, with the results of some studies suggesting racial or ethnic differences inExpand
Applying Causal Inference Methods in Psychiatric Epidemiology: A Review.
Of the large family of statistical methods for causal inference, propensity scoring and marginal models are examined, which are best applied to samples with strong predictors of risk factor exposure and are important because it informs etiologic models and prevention efforts. Expand