Summary
Three-prime repair exonuclease I (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.
Reciprocal deletion and duplication of the 16p11.2 region is the most common copy number variation (CNV) associated with autism spectrum disorders. We generated cortical organoids from skin fibroblasts of patients with 16p11.2 CNV to investigate impacted neurodevelopmental processes. We show that organoid size recapitulates macrocephaly and microcephaly phenotypes observed in the patients with 16p11.2 deletions and duplications. The CNV dosage affects neuronal maturation, proliferation, and synapse number, in addition to its effect on organoid size. We demonstrate that 16p11.2 CNV alters the ratio of neurons to neural progenitors in organoids during early neurogenesis, with a significant excess of neurons and depletion of neural progenitors observed in deletions. Transcriptomic and proteomic profiling revealed multiple pathways dysregulated by the 16p11.2 CNV, including neuron migration, actin cytoskeleton, ion channel activity, synaptic-related functions, and Wnt signaling. The level of the active form of small GTPase RhoA was increased in both, deletions and duplications. Inhibition of RhoA activity rescued migration deficits, but not neurite outgrowth. This study provides insights into potential neurobiological mechanisms behind the 16p11.2 CNV during neocortical development.
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