Interferon-driven brain phenotype in a mouse model of RNaseT2 deficient leukoencephalopathy

Matthias Kettwig, Katharina Ternka, Kristin Wendland, Dennis Manfred Krueger, Silvia Zampar, Charlotte Schob, Jonas Franz, Abhishek Aich, Anne Winkler, M. Sadman Sakib, Lalit Kaurani, Robert Epple, Hauke B. Werner, Samy Hakroush, Julia Kitz, Marco Prinz, Eva Bartok, Gunther Hartmann, Simone Schroeder, Peter RehlingMarco Henneke, Susann Boretius, A. Alia, Oliver Wirths, Andre Fischer, Christine Stadelmann, Stefan Nessler, Jutta Gaertner

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    Abstract

    Infantile-onset RNaseT2 deficient leukoencephalopathy is characterised by cystic brain lesions, multifocal white matter alterations, cerebral atrophy, and severe psychomotor impairment. The phenotype is similar to congenital cytomegalovirus brain infection and overlaps with type I interferonopathies, suggesting a role for innate immunity in its pathophysiology. To date, pathophysiological studies have been hindered by the lack of mouse models recapitulating the neuroinflammatory encephalopathy found in patients. In this study, we generated Rnaset2 -/- mice using CRISPR/Cas9-mediated genome editing. Rnaset2 -/- mice demonstrate upregulation of interferon-stimulated genes and concurrent IFNAR1-dependent neuroinflammation, with infiltration of CD8 + effector memory T cells and inflammatory monocytes into the grey and white matter. Single nuclei RNA sequencing reveals homeostatic dysfunctions in glial cells and neurons and provide important insights into the mechanisms of hippocampal-accentuated brain atrophy and cognitive impairment. The Rnaset2 -/- mice may allow the study of CNS damage associated with RNaseT2 deficiency and may be used for the investigation of potential therapies.

    Original languageEnglish
    Article number6530
    JournalNature Communications
    Volume12
    Issue number1
    Number of pages18
    ISSN2041-1723
    DOIs
    Publication statusPublished - 2021

    Keywords

    • CD8 T-CELLS
    • CENTRAL-NERVOUS-SYSTEM
    • CYSTIC LEUKOENCEPHALOPATHY
    • AUTOIMMUNE DISORDERS
    • LUPUS-ERYTHEMATOSUS
    • MICE
    • MUTATIONS
    • MEMORY
    • TREX1
    • RNA

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