Modeling of TREX1-Dependent Autoimmune Disease using Human Stem Cells Highlights L1 Accumulation as a Source of Neuroinflammation

Publication date: Available online 10 August 2017
Source:Cell Stem Cell
Author(s): Charles A. Thomas, Leon Tejwani, Cleber A. Trujillo, Priscilla D. Negraes, Roberto H. Herai, Pinar Mesci, Angela Macia, Yanick J. Crow, Alysson R. Muotri
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-Goutières 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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Teaser

Thomas et al. used human pluripotent stem cells to dissect the contribution of neurons and glia to the neuroinflammatory disorder Aicardi-Goutières syndrome (AGS). They found that mutant cells accumulate retroviral-like extrachromosomal nucleic acids that trigger a neurotoxic response, and they suggest that anti-retrovirals could potentially provide therapy for this disease.


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