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Upregulation of non-canonical and canonical inflammasome genes associates with pathological features in Krabbe disease and related disorders.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Cachón-González, María B  ORCID logo  https://orcid.org/0000-0002-1884-2527
Zhao, Chao 
Franklin, Robin J 
Cox, Timothy M 

Abstract

Infantile Krabbe disease is a rapidly progressive and fatal disorder of myelin, caused by inherited deficiency of the lysosomal enzyme β-galactocerebrosidase. Affected children lose their motor skills and other faculties; uncontrolled seizures are a frequent terminal event. Overexpression of the sphingolipid metabolite psychosine is a pathogenic factor, but does not fully account for the pleiotropic manifestations and there is a clear need to investigate additional pathological mechanisms. We examined innate immunity, caspase-11 and associated inflammatory pathways in twitcher mice, an authentic model of Krabbe disease. Combined use of molecular tools, RNAscope in situ hybridization and immunohistochemical staining established that the expression of pro-inflammatory non-canonical caspase-11, canonical caspase-1, gasdermin D and cognate genes is induced in nervous tissue. Early onset and progressive upregulation of these genes accompany demyelination and gliosis and although the molecules are scant in healthy tissue, abundance of the respective translation products is greatly increased in diseased animals. Caspase-11 is found in reactive microglia/macrophages as well as astrocytes but caspase-1 and gasdermin D are restricted to reactive microglia/macrophages. The inflammasome signature is not unique to Krabbe disease; to varying degrees, this signature is also prominent in other lysosomal diseases, Sandhoff and Niemann-Pick Type-C1, and the lysolecithin toxin model of focal demyelination. Given the potent inflammatory response here identified in Krabbe disease and the other neurodegenerative disorders studied, a broad induction of inflammasomes is likely to be a dominant factor in the pathogenesis, and thus represents a platform for therapeutic exploration.

Description

Keywords

Mice, Animals, Leukodystrophy, Globoid Cell, Inflammasomes, Up-Regulation, Gasdermins, Disease Models, Animal, Psychosine, Caspases

Journal Title

Hum Mol Genet

Conference Name

Journal ISSN

0964-6906
1460-2083

Volume Title

Publisher

Oxford University Press (OUP)
Sponsorship
Cambridge University Hospitals NHS Foundation Trust (CUH) (RG50826 METABOLISM)
National Institute for Health Research (NIHR) (unknown)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Wellcome Trust (203151/Z/16/Z)
National Institute for Health and Care Research (IS-BRC-1215-20014)