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

Abstract

<i>Alu</i> retroelements propagate via retrotransposition by hijacking long interspersed nuclear element-1 (L1) reverse transcriptase (RT) and endonuclease activities. Reverse transcription of <i>Alu</i> RNA into complementary DNA (cDNA) is presumed to occur exclusively in the nucleus at the genomic integration site. Whether <i>Alu</i> cDNA is synthesized independently of genomic integration is unknown. <i>Alu</i> RNA promotes retinal pigmented epithelium (RPE) death in geographic atrophy, an untreatable type of age-related macular degeneration. We report that <i>Alu</i> RNA-induced RPE degeneration is mediated via cytoplasmic L1-reverse-transcribed <i>Alu</i> cDNA independently of retrotransposition. <i>Alu</i> RNA did not induce cDNA production or RPE degeneration in L1-inhibited animals or human cells. <i>Alu</i> reverse transcription can be initiated in the cytoplasm via self-priming of <i>Alu</i> 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 <i>Alu</i> replication cycle shunt as potential therapies for a major cause of blindness.