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  • DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes.

DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes.

The Journal of experimental medicine (2022-03-10)
Anna Maria Sole Giordano, Marco Luciani, Francesca Gatto, Monah Abou Alezz, Chiara Beghè, Lucrezia Della Volpe, Alessandro Migliara, Sara Valsoni, Marco Genua, Monika Dzieciatkowska, Giacomo Frati, Julie Tahraoui-Bories, Silvia Clara Giliani, Simona Orcesi, Elisa Fazzi, Renato Ostuni, Angelo D'Alessandro, Raffaella Di Micco, Ivan Merelli, Angelo Lombardo, Martin A M Reijns, Natalia Gromak, Angela Gritti, Anna Kajaste-Rudnitski
ABSTRACT

Aberrant induction of type I IFN is a hallmark of the inherited encephalopathy Aicardi-Goutières syndrome (AGS), but the mechanisms triggering disease in the human central nervous system (CNS) remain elusive. Here, we generated human models of AGS using genetically modified and patient-derived pluripotent stem cells harboring TREX1 or RNASEH2B loss-of-function alleles. Genome-wide transcriptomic analysis reveals that spontaneous proinflammatory activation in AGS astrocytes initiates signaling cascades impacting multiple CNS cell subsets analyzed at the single-cell level. We identify accumulating DNA damage, with elevated R-loop and micronuclei formation, as a driver of STING- and NLRP3-related inflammatory responses leading to the secretion of neurotoxic mediators. Importantly, pharmacological inhibition of proapoptotic or inflammatory cascades in AGS astrocytes prevents neurotoxicity without apparent impact on their increased type I IFN responses. Together, our work identifies DNA damage as a major driver of neurotoxic inflammation in AGS astrocytes, suggests a role for AGS gene products in R-loop homeostasis, and identifies common denominators of disease that can be targeted to prevent astrocyte-mediated neurotoxicity in AGS.

MATERIALS
Product Number
Brand
Product Description

Roche
DAPI, 4′,6-Diamidine-2′-phenylindole dihydrochloride
Sigma-Aldrich
Anti-DNA Antibody, single stranded, clone 16-19, clone 16-19, Chemicon®, from mouse
Sigma-Aldrich
Albumin, Acetylated from bovine serum, protease free, for molecular biology