Modeling of TREX1-Dependent Autoimmune Disease using Human Stem Cells Highlights L1 Accumulation as a Source of Neuroinflammation.
Cell Stem Cell
; 21(3): 319-331.e8, 2017 09 07.
Article
en En
| MEDLINE
| ID: mdl-28803918
ABSTRACT
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Fosfoproteínas
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Enfermedades Autoinmunes
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Células Madre
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Elementos de Nucleótido Esparcido Largo
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Exodesoxirribonucleasas
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Inflamación
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Sistema Nervioso
Límite:
Child
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Humans
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Infant
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Male
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Newborn
Idioma:
En
Año:
2017
Tipo del documento:
Article