Abstract
Krabbe disease, one of the autosomal-recessive lysosomal storage disorders (LSDs), is caused by a deficiency of galactocerebrosidase (GALC) activity, resulting in the intracellular accumulation of psychosine, which is cytotoxic for neuronal cells. Genetically pathogenic mutations result in conformational changes in GALC and disrupt the lysosmal trafficking of cargos, which subsequently accumulate in the endoplasmic reticulum (ER). Recently, ER stress together with the activation of the unfolded protein response (UPR) has been suggested to play a key role in the pathogenesis of LSDs. In this study, we hence investigated whether the UPR is activated in Krabbe disease using COS-7 cells expressing pathogenic GALC mutants and skin fibroblasts (SFs) from Krabbe disease patients with various phenotypes, using a combination of semiquantitative and quantitative real-time polymerase chain reactions. We found that UPR activation in Krabbe disease depends on the mutations and cell types, and there is the possibility that multiple pathways, involving ER chaperones, inositol-requiring kinase 1, and protein kinase regulated by RNA-like ER kinase are activated by mutations associated with the infantile form. These results indicate that in Krabbe disease, each misfolded/unfolded protein evokes different UPR activation depending on the mutation, and that the activated pathways affect the phenotypes.
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Acknowledgements
We thank the patients and their families for their participation in this study. We thank K. Tsujimoto (Osaka University) for technical assistance. This work was supported by the Practical Research Project for Rare/Intractable Diseases (15ek0109151h003) from Japan Agency for Medical Research and Development (AMED), and a Health and Labour Sciences Research Grants (H29-nanchitou (nan)-ippan-024) from Ministry of Health, Labour and Welfare.
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Irahara-Miyana, K., Otomo, T., Kondo, H. et al. Unfolded protein response is activated in Krabbe disease in a manner dependent on the mutation type. J Hum Genet 63, 699–706 (2018). https://doi.org/10.1038/s10038-018-0445-8
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DOI: https://doi.org/10.1038/s10038-018-0445-8
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