TY  - JOUR
AU  - Kettwig, Matthias
AU  - Ternka, Katharina
AU  - Wendland, Kristin
AU  - Krüger, Dennis Manfred
AU  - Zampar, Silvia
AU  - Schob, Charlotte
AU  - Franz, Jonas
AU  - Aich, Abhishek
AU  - Winkler, Anne
AU  - Sakib, M Sadman
AU  - Kaurani, Lalit
AU  - Epple, Robert
AU  - Werner, Hauke B
AU  - Hakroush, Samy
AU  - Kitz, Julia
AU  - Prinz, Marco
AU  - Bartok, Eva
AU  - Hartmann, Gunther
AU  - Schröder, Simone
AU  - Rehling, Peter
AU  - Henneke, Marco
AU  - Boretius, Susann
AU  - Alia, A.
AU  - Wirths, Oliver
AU  - Fischer, Andre
AU  - Stadelmann, Christine
AU  - Nessler, Stefan
AU  - Gärtner, Jutta
TI  - Interferon-driven brain phenotype in a mouse model of RNaseT2 deficient leukoencephalopathy.
JO  - Nature Communications
VL  - 12
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2022-00210
SP  - 6530
PY  - 2021
N1  - (CC BY)
AB  - 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.
KW  - Animals
KW  - CD8-Positive T-Lymphocytes: metabolism
KW  - Cognitive Dysfunction: genetics
KW  - Cognitive Dysfunction: metabolism
KW  - Disease Models, Animal
KW  - Endoribonucleases: genetics
KW  - Endoribonucleases: metabolism
KW  - Female
KW  - Flow Cytometry
KW  - Genotype
KW  - Humans
KW  - Immunohistochemistry
KW  - Leukoencephalopathies: genetics
KW  - Leukoencephalopathies: metabolism
KW  - Leukoencephalopathies: pathology
KW  - Magnetic Resonance Imaging
KW  - Male
KW  - Memory T Cells: metabolism
KW  - Mice
KW  - Mice, Knockout
KW  - Neuroglia: metabolism
KW  - Real-Time Polymerase Chain Reaction
KW  - Endoribonucleases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:34764281
C2  - pmc:PMC8586222
DO  - DOI:10.1038/s41467-021-26880-x
UR  - https://pub.dzne.de/record/163450
ER  -