Journal
CELL STEM CELL
Volume 21, Issue 3, Pages 319-+Publisher
CELL PRESS
DOI: 10.1016/j.stem.2017.07.009
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Funding
- NIH [R01MH108528, R01MH094753, R01MH109885, R01MH100175, R21MH107771, R56MH109587, U19MH107367]
- Ruth L. Kirschstein NRSA Fellowship [1F31NS076198]
- California Institute for Regenerative Medicine (CIRM) award [DISC1-08825]
- UCSD CTRI pilot grant
- NARSAD Independent Investigator Grant
- European Research Council [GA 309449]
- ERA-NET Neuron [MR/M501803/1]
- National Research Agency (France) [ANR-10-IAHU-01]
- Roche Postdoc Fellowship Program (F. Hoffmann-La Roche)
- Medical Research Council [MR/M501803/1] Funding Source: researchfish
- MRC [MR/M501803/1] Funding Source: UKRI
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Three-prime repair exonuclease 1 (TREX1) is an anti-viral enzyme that cleaves nucleic acids in the cytosol, preventing accumulation and a subsequent type I interferon-associated inflammatory response. Autoimmune diseases, including Aicardi-Goutieres syndrome (AGS) and systemic lupus erythematosus, can arise when TREX1 function is compromised. AGS is a neuroinflammatory disorder with severe and persistent intellectual and physical problems. Here we generated a human AGS model that recapitulates disease-relevant phenotypes using pluripotent stem cells lacking TREX1. We observed abundant extrachromosomal DNA in TREX1-deficient neural cells, of which endogenous Long Interspersed Element-1 retrotransposons were a major source. TREX1-deficient neurons also exhibited increased apoptosis and formed three-dimensional cortical organoids of reduced size. TREX1-deficient astrocytes further contributed to the observed neurotoxicity through increased type I interferon secretion. In this model, reverse-transcriptase inhibitors rescued the neurotoxicity of AGS neurons and organoids, highlighting their potential utility in therapeutic regimens for AGS and related disorders.
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