Microgliosis and aberrant interferon response in Adar Mavs
brain are rescued by PKR removal

J 2026

Microgliosis and aberrant interferon response in Adar Mavs brain are rescued by PKR removal

LACOVICH STRAŠIL, Valentina; Stanislav STEJSKAL; Kristina LOCKER KOVAČOVICOVA; David POTĚŠIL; Václav PUSTKA et al.

Základní údaje

Originální název

Microgliosis and aberrant interferon response in Adar Mavs brain are rescued by PKR removal

Autoři

Vydání

BRAIN, OXFORD UNIV PRESS, 2026, 0006-8950

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 11.700 v roce 2024

Označené pro přenos do RIV

Ano

Organizační jednotka

Středoevropský technologický institut

Klíčová slova anglicky

innate immunity; ADAR1; Aicardi–Goutières syndrome 6; PKR; microglia; neuroinflammation

Štítky

143160

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 12. 3. 2026 14:54, Mgr. Marie Novosadová Šípková, DiS.

Anotace

V originále

Mutations in the human ADAR gene encoding adenosine deaminase acting on RNA 1 (ADAR1) cause Aicardi-Goutières syndrome 6 (AGS6); a severe auto-inflammatory encephalopathy with aberrant interferon (IFN) induction. AdarΔ2-13 null mutant mouse embryos lacking ADAR1 protein die with high levels of IFN-stimulated gene (ISG) transcripts. In Adar Mavs double mutants also lacking the Mitochondrial antiviral signaling (MAVS) adaptor, the aberrant IFN induction is prevented. Live pups are born and survive for two weeks, allowing ADAR1 function to be investigated. We have shown that early death of Adar Mavs mutants is rescued by the deletion of the Eif2ak2 gene encoding the antiviral dsRNA sensor protein kinase R (PKR). Here, we focused on characterizing the brain defects in Adar Mavs mutants and their dependencies on PKR. Mouse brains were collected on postnatal days 8 and 14, analysed by mass spectrometry, immunohistochemistry and RT-qPCR. The proteomic analyses showed upregulation of ISG-encoded proteins in the Adar Mavs double mutant and the morphological analyses confirmed the aberrant microgliosis in brains. Both are prevented in Adar Mavs Eif2ak2 triple mutants, indicating the key role of aberrant PKR activation; PKR expression is also increased by IFN signaling. Altered expression levels of transcripts encoding differentially expressed proteins and of ADAR-edited transcripts were confirmed by RT-qPCR. Analysis of the expression levels of transcripts in the brains of mutants expressing a catalytically-inactive ADAR E861A protein, revealed that the levels of some but not all altered transcripts are restored. A further group of proteins, downregulated in Adar Mavs are not rescued by removing PKR and may result from effects of loss of the widespread ADAR1 RNA editing known to occur in brain transcripts. This group includes several motor proteins, some of which have been reported to be encoded by ADAR-edited transcripts. In this study we show Adar Mavs double mutants exhibit an aberrant IFN response in the brain likely due to reactive microglia and astrocytes. Microgliosis, which is rescued in the triple mutant, is mostly dependent on aberrant PKR activation and is partially RNA-editing dependent.

Návaznosti

GX21-27329X, projekt VaV

Název: ADAR-dependentní RNA editace; Jak imunitní systém a mozek porušují Centrální Dogma.

Investor: Grantová agentura ČR, ADAR RNA editing, how immune systems and brains breach The Central Dogma

LM2023042, projekt VaV

Název: Česká infrastruktura pro integrativní strukturní biologii

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CIISB - Česká infrastruktura pro integrativní strukturní biologii

90254, velká výzkumná infrastruktura

Název: e-INFRA CZ II

Citovat

LACOVICH STRAŠIL, Valentina; Stanislav STEJSKAL; Kristina LOCKER KOVAČOVICOVA; David POTĚŠIL; Václav PUSTKA; Dragana VUKIĆ; Katerina TEXLOVA; Pavla MUSILOVÁ; Janka MELICHEROVÁ; Ketty SINIGAGLIA; Daniel HAVAS; Liam KEEGAN a Mary Anne O'CONNELL. Microgliosis and aberrant interferon response in Adar Mavs brain are rescued by PKR removal. BRAIN. OXFORD UNIV PRESS, 2026, roč. 149, č. 2, s. 456-471. ISSN 0006-8950. Dostupné z: https://doi.org/10.1093/brain/awaf315.

@article{2516877,
   author = {Lacovich Strašil, Valentina and Stejskal, Stanislav and Locker Kovačovicova, Kristina and Potěšil, David and Pustka, Václav and Vukić, Dragana and Texlova, Katerina and Musilová, Pavla and Melicherová, Janka and Sinigaglia, Ketty and Havas, Daniel and Keegan, Liam and O'Connell, Mary Anne},
   article_number = {2},
   doi = {https://doi.org/10.1093/brain/awaf315},
   keywords = {innate immunity; ADAR1; Aicardi–Goutières syndrome 6; PKR; microglia; neuroinflammation},
   language = {eng},
   issn = {0006-8950},
   journal = {BRAIN},
   title = {Microgliosis and aberrant interferon response in Adar Mavs brain are rescued by PKR removal},
   url = {https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf315/8249110},
   volume = {149},
   year = {2026}
}

TY  - JOUR
ID  - 2516877
AU  - Lacovich Strašil, Valentina - Stejskal, Stanislav - Locker Kovačovicova, Kristina - Potěšil, David - Pustka, Václav - Vukić, Dragana - Texlova, Katerina - Musilová, Pavla - Melicherová, Janka - Sinigaglia, Ketty - Havas, Daniel - Keegan, Liam - O'Connell, Mary Anne
PY  - 2026
TI  - Microgliosis and aberrant interferon response in Adar Mavs brain are rescued by PKR removal
JF  - BRAIN
VL  - 149
IS  - 2
SP  - 456-471
EP  - 456-471
PB  - OXFORD UNIV PRESS
SN  - 00068950
KW  - innate immunity
KW  - ADAR1
KW  - Aicardi–Goutières syndrome 6
KW  - PKR
KW  - microglia
KW  - neuroinflammation
UR  - https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf315/8249110
N2  - Mutations in the human ADAR gene encoding adenosine deaminase acting on RNA 1 (ADAR1) cause Aicardi-Goutières syndrome 6 (AGS6); a severe auto-inflammatory encephalopathy with aberrant interferon (IFN) induction. AdarΔ2-13 null mutant mouse embryos lacking ADAR1 protein die with high levels of IFN-stimulated gene (ISG) transcripts. In Adar Mavs double mutants also lacking the Mitochondrial antiviral signaling (MAVS) adaptor, the aberrant IFN induction is prevented. Live pups are born and survive for two weeks, allowing ADAR1 function to be investigated. We have shown that early death of Adar Mavs mutants is rescued by the deletion of the Eif2ak2 gene encoding the antiviral dsRNA sensor protein kinase R (PKR). Here, we focused on characterizing the brain defects in Adar Mavs mutants and their dependencies on PKR. Mouse brains were collected on postnatal days 8 and 14, analysed by mass spectrometry, immunohistochemistry and RT-qPCR. The proteomic analyses showed upregulation of ISG-encoded proteins in the Adar Mavs double mutant and the morphological analyses confirmed the aberrant microgliosis in brains. Both are prevented in Adar Mavs Eif2ak2 triple mutants, indicating the key role of aberrant PKR activation; PKR expression is also increased by IFN signaling. Altered expression levels of transcripts encoding differentially expressed proteins and of ADAR-edited transcripts were confirmed by RT-qPCR. Analysis of the expression levels of transcripts in the brains of mutants expressing a catalytically-inactive ADAR E861A protein, revealed that the levels of some but not all altered transcripts are restored. A further group of proteins, downregulated in Adar Mavs are not rescued by removing PKR and may result from effects of loss of the widespread ADAR1 RNA editing known to occur in brain transcripts. This group includes several motor proteins, some of which have been reported to be encoded by ADAR-edited transcripts. In this study we show Adar Mavs double mutants exhibit an aberrant IFN response in the brain likely due to reactive microglia and astrocytes. Microgliosis, which is rescued in the triple mutant, is mostly dependent on aberrant PKR activation and is partially RNA-editing dependent.
ER  -

LACOVICH STRAŠIL, Valentina; Stanislav STEJSKAL; Kristina LOCKER KOVAČOVICOVA; David POTĚŠIL; Václav PUSTKA; Dragana VUKI$\backslash$'C; Katerina TEXLOVA; Pavla MUSILOVÁ; Janka MELICHEROVÁ; Ketty SINIGAGLIA; Daniel HAVAS; Liam KEEGAN a Mary Anne O'CONNELL. Microgliosis and aberrant interferon response in Adar Mavs brain are rescued by PKR removal. \textit{BRAIN}. OXFORD UNIV PRESS, 2026, roč.~149, č.~2, s.~456-471. ISSN~0006-8950. Dostupné z: https://doi.org/10.1093/brain/awaf315.

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