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Expression of Ripk1 and DAM genes correlates with severity and progression of Krabbe disease.

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Cachón-González, María B  ORCID logo
Wang, Susan 
Cox, Timothy M 


Krabbe disease, an inherited leukodystrophy, is a sphingolipidosis caused by deficiency of β-galactocerebrosidase: it is characterized by myelin loss, and pathological activation of macrophage/microglia and astrocytes. To define driving pathogenic factors, we explored the expression repertoire of candidate neuroinflammatory genes: upregulation of receptor interacting protein kinase 1 (Ripk1) and disease-associated microglia (DAM) genes, including Cst7 and Ch25h, correlated with severity of Krabbe disease genetically modelled in the twitcher mouse. Upregulation of Ripk1 in Iba1/Mac2-positive microglia/macrophage associated with the pathognomic hypertrophic/globoid phenotype of this disease. Widespread accumulation of ubiquitinin1 in white and grey matter co-localised with p62. In Sandhoff disease, another sphingolipid disorder, neuroinflammation, accumulation of p62 and increased Ripk1 expression was observed. The upregulated DAM genes and macrophage/microglia expression of Ripk1 in the authentic model of Krabbe disease strongly resemble those reported in Alzheimer disease associating with disturbed autophagosomal/lysosomal homeostasis. Activation of this shared molecular repertoire, suggests the potential for therapeutic interdiction at a common activation step, irrespective of proximal causation. To clarify the role of Ripk1 in the pathogenesis of Krabbe disease, we first explored the contribution of its kinase function, by intercrossing twitcher and the K45A kinase-dead Ripk1 mouse and breeding to homozygosity. Genetic ablation of Ripk1 kinase activity neither altered the neuropathological features nor the survival of twitcher mice. We conclude that Ripk1 kinase-dependent inflammatory and degenerative capabilities play no instrumental role in Krabbe disease; however, putative kinase-independent functions of Ripk1 remain formally to be explored in its molecular pathogenesis.



Animals, Autophagosomes, Biomarkers, Disease Models, Animal, Disease Progression, Disease Susceptibility, Gene Expression, Gene Knockdown Techniques, Humans, Leukodystrophy, Globoid Cell, Mice, Microglia, Neuroinflammatory Diseases, Protein Transport, Receptor-Interacting Protein Serine-Threonine Kinases, Severity of Illness Index, Transcriptome

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Hum Mol Genet

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Oxford University Press (OUP)


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Cambridge University Hospitals NHS Foundation Trust (CUH) (RG50826 METABOLISM)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Sparks: The Children's Medical Research Charity (14CAM03)
National Institute for Health and Care Research (IS-BRC-1215-20014)
NIHR Cambridge Biomedical Research Centre [grant number IS-BRC-1215-20014]; and Sparks [grant number 14CAM03]