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

Matthias Kettwig (), Katharina Ternka, Kristin Wendland, Dennis Manfred Krüger, 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 Schröder, Peter Rehling, Marco Henneke, Susann Boretius, A. Alia, Oliver Wirths, Andre Fischer, Christine Stadelmann, Stefan Nessler and Jutta Gärtner
Additional contact information
Matthias Kettwig: University Medical Center Göttingen, Georg August University
Katharina Ternka: University Medical Center Göttingen, Georg August University
Kristin Wendland: University Medical Center Göttingen, Georg August University
Dennis Manfred Krüger: German Center for Neurodegenerative Diseases (DZNE)
Silvia Zampar: University Medical Center Göttingen, Georg August University
Charlotte Schob: University Medical Center Göttingen, Georg August University
Jonas Franz: University Medical Center Göttingen, Georg August University
Abhishek Aich: University Medical Center Göttingen, Georg August University
Anne Winkler: University Medical Center Göttingen, Georg August University
M. Sadman Sakib: German Center for Neurodegenerative Diseases (DZNE)
Lalit Kaurani: German Center for Neurodegenerative Diseases (DZNE)
Robert Epple: German Center for Neurodegenerative Diseases (DZNE)
Hauke B. Werner: Max Planck Institute of Experimental Medicine
Samy Hakroush: University Medical Center Göttingen, Georg August University
Julia Kitz: University Medical Center Göttingen, Georg August University
Marco Prinz: University of Freiburg
Eva Bartok: University Hospital, University of Bonn
Gunther Hartmann: University Hospital, University of Bonn
Simone Schröder: University Medical Center Göttingen, Georg August University
Peter Rehling: University Medical Center Göttingen, Georg August University
Marco Henneke: University Medical Center Göttingen, Georg August University
Susann Boretius: Leibniz Institute for Primate Research
A. Alia: University of Leipzig
Oliver Wirths: University Medical Center Göttingen, Georg August University
Andre Fischer: German Center for Neurodegenerative Diseases (DZNE)
Christine Stadelmann: University Medical Center Göttingen, Georg August University
Stefan Nessler: University Medical Center Göttingen, Georg August University
Jutta Gärtner: University Medical Center Göttingen, Georg August University

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26880-x

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