title: Chaperone therapy for Krabbe disease: potential for late-onset GALC mutations.
abstract: Krabbe disease is an autosomal recessive leukodystrophy caused by a deficiency of the galactocerebrosidase (GALC) enzyme. Hematopoietic stem cells transplantation is the only available treatment option for pre-symptomatic patients. We have previously reported the chaperone effect of N-octyl-4-epi-β-valienamine (NOEV) on mutant GM1 β-galactosidase proteins, and in a murine GM1-gangliosidosis model. In this study, we examined its chaperone effect on mutant GALC proteins. We found that NOEV strongly inhibited GALC activity in cell lysates of GALC-transfected COS1 cells. In vitro NOEV treatment stabilized GALC activity under heat denaturation conditions. We also examined the effect of NOEV on cultured COS1 cells expressing mutant GALC activity and human skin fibroblasts from Krabbe disease patients: NOEV significantly increased the enzyme activity of mutants of late-onset forms. Moreover, we confirmed that NOEV could enhance the maturation of GALC precursor to its mature active form. Model structural analysis showed NOEV binds to the active site of human GALC protein. These results, for the first time, provide clear evidence that NOEV is a chaperone with promising potential for patients with Krabbe disease resulting from the late-onset mutations.
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Mohammad Arif
authors.initials: MA
authors.lastname: Hossain
authors.affiliation: Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, Yonago, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Higaki
authors.affiliation: Department of Medical Management and Informatics, Hokkaido Information University, Hokkaido, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Saito
authors.affiliation: NPO for the Promotion of Research on Intellectual Property Tokyo, Tokyo, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Ohno
authors.affiliation: Department of Clinical Genetics, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sakuraba
authors.affiliation: Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, Yonago, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Nanba
authors.affiliation: Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ozono
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Sakai
mesh_terms: D000328:Adult; D017668:Age of Onset; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002648:Child; D002522:Chlorocebus aethiops; D004353:Drug Evaluation, Preclinical; D005698:Galactosylceramidase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D006595:Hexosamines / Q000627:therapeutic use*; D006801:Humans; D007223:Infant; D007965:Leukodystrophy, Globoid Cell / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018832:Molecular Chaperones / Q000627:therapeutic use
chemical_list: D006595:Hexosamines; D018832:Molecular Chaperones; C116532:N-octyl-beta-valienamine; D005698:Galactosylceramidase