Alu complementary DNA is enriched in atrophic macular degeneration and triggers retinal pigmented epithelium toxicity via cytosolic innate immunity.

Details

Serval ID
serval:BIB_19971A01C1BC
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Alu complementary DNA is enriched in atrophic macular degeneration and triggers retinal pigmented epithelium toxicity via cytosolic innate immunity.
Journal
Science advances
Author(s)
Fukuda S., Narendran S., Varshney A., Nagasaka Y., Wang S.B., Ambati K., Apicella I., Pereira F., Fowler B.J., Yasuma T., Hirahara S., Yasuma R., Huang P., Yerramothu P., Makin R.D., Wang M., Baker K.L., Marion K.M., Huang X., Baghdasaryan E., Ambati M., Ambati V.L., Banerjee D., Bonilha V.L., Tolstonog G.V., Held U., Ogura Y., Terasaki H., Oshika T., Bhattarai D., Kim K.B., Feldman S.H., Aguirre J.I., Hinton D.R., Kerur N., Sadda S.R., Schumann G.G., Gelfand B.D., Ambati J.
ISSN
2375-2548 (Electronic)
ISSN-L
2375-2548
Publication state
Published
Issued date
10/2021
Peer-reviewed
Oui
Volume
7
Number
40
Pages
eabj3658
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Long interspersed nuclear element-1 (L1)-mediated reverse transcription (RT) of AN RNA into cytoplasmic AN complementary DNA (cDNA) has been implicated in retinal pigmented epithelium (RPE) degeneration. The mechanism of AN cDNA-induced cytotoxicity and its relevance to human disease are unknown. Here we report that AN cDNA is highly enriched in the RPE of human eyes with geographic atrophy, an untreatable form of age-related macular degeneration. We demonstrate that the DNA sensor cGAS engages Alu cDNA to induce cytosolic mitochondria! DNA escape, which amplifies cGAS activation, triggering RPE degeneration via the inflammasome. The L1-extinct rice rat was resistant to AN RNA-inducedAlu cDNA synthesis and RPE degeneration, which were enabled upon L1-RT overexpression. Nucleoside RT inhibitors (NRTIs), which inhibit both L1-RT and inflammasome activity, and NRTI derivatives (Kamuvudines) that inhibit inflammasome, but not RT, both block AN cDNA toxicity, identifying inflammasome activation as the terminal effector of RPE degeneration.
Pubmed
Web of science
Open Access
Yes
Create date
04/10/2021 8:10
Last modification date
16/10/2021 5:34
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