Journal Article

DZNE-2022-00210

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Interferon-driven brain phenotype in a mouse model of RNaseT2 deficient leukoencephalopathy.

Kettwig, M. ; Ternka, K. ; Wendland, K. ; Krüger, D. M.DZNE* ; Zampar, S. ; Schob, C. ; Franz, J. ; Aich, A. ; Winkler, A. ; Sakib, M. S.DZNE* ; Kaurani, L.DZNE* ; Epple, R.DZNE* ; Werner, H. B. ; Hakroush, S. ; Kitz, J. ; Prinz, M. ; Bartok, E. ; Hartmann, G. ; Schröder, S. ; Rehling, P. ; Henneke, M. ; Boretius, S. ; Alia, A. ; Wirths, O. ; Fischer, A.DZNE* ; Stadelmann, C.Extern* ; Nessler, S. ; Gärtner, J.Extern*

2021
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-021-26880-x

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.

Keyword(s): Animals (MeSH) ; CD8-Positive T-Lymphocytes: metabolism (MeSH) ; Cognitive Dysfunction: genetics (MeSH) ; Cognitive Dysfunction: metabolism (MeSH) ; Disease Models, Animal (MeSH) ; Endoribonucleases: genetics (MeSH) ; Endoribonucleases: metabolism (MeSH) ; Female (MeSH) ; Flow Cytometry (MeSH) ; Genotype (MeSH) ; Humans (MeSH) ; Immunohistochemistry (MeSH) ; Leukoencephalopathies: genetics (MeSH) ; Leukoencephalopathies: metabolism (MeSH) ; Leukoencephalopathies: pathology (MeSH) ; Magnetic Resonance Imaging (MeSH) ; Male (MeSH) ; Memory T Cells: metabolism (MeSH) ; Mice (MeSH) ; Mice, Knockout (MeSH) ; Neuroglia: metabolism (MeSH) ; Real-Time Polymerase Chain Reaction (MeSH) ; Endoribonucleases

Note: (CC BY)

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Contributing Institute(s):

1. Bioinformatics and Genome Dynamics Core (Bioinformatics and Genome Dynamics Core)
2. Epigenetics and Systems Medicine in Neurodegenerative Diseases (AG Fischer)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2021

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