title: Effect of vitamin D3 intake on the onset of disease in a murine model of human Krabbe disease.
abstract: Low vitamin D level is a risk factor for various late-onset CNS demyelinating disorders. We investigated whether vitamin D deficiency influences disease in twitcher mice (GALC(twi/twi) ; twi), a murine model of Krabbe disease (KD), an inherited disorder caused by galactocerebrosidase (GALC) deficiency that leads to psychosine accumulation, oligodendrocyte (OL) loss, and CNS demyelination. We found that the in situ 1,25-dihydroxyvitamin D3 level was reduced, with a parallel increase in the expression of inflammatory cytokines and vitamin D-catabolizing enzymes in the brains of KD and twi mice compared with age-matched controls. Pups maintained on milk from lactating heterozygous (GALC(twi/+) ) mothers that were fed a vitamin D3-supplemented diet until weaning and then fed a vitamin D3-supplemented diet demonstrated delayed body weight loss and development of disease in twi mice. This delayed the onset of tremors and locomotor disabilities that eventually impacted the life span of twi mice (50 ± 2 days). Accordingly, the expression of antioxidant enzymes was increased with delayed psychosine accumulation, lipid peroxidation, and inflammatory response that eventually protected CNS myelin and axonal integrity in twi mice. In vitro studies revealed that 1,25-dihydroxyvitamin D3 enhances antioxidant defenses in OLs deficient for GALC or incubated with psychosine. Together these data provide the first evidence that vitamin D deficiency affects disease development in twi mice and that vitamin D3 supplementation has the potential to improve the efficacy of KD therapeutics.
authors.affiliation: Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Manjeet K
authors.initials: MK
authors.lastname: Paintlia
authors.forename: Inderjit
authors.initials: I
authors.lastname: Singh
authors.forename: Avtar K
authors.initials: AK
authors.lastname: Singh
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002117:Calcitriol / Q000008:administration & dosage / Q000378:metabolism*; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000378:metabolism / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005698:Galactosylceramidase / Q000172:deficiency; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007965:Leukodystrophy, Globoid Cell / Q000178:diet therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008817:Mice, Mutant Strains; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002762:Cholecalciferol; D016207:Cytokines; D005698:Galactosylceramidase; D005978:Glutathione; D004676:Myelin Basic Protein; D013482:Superoxide Dismutase; D065668:Vitamin D3 24-Hydroxylase; D000099156:Superoxide Dismutase 2
keywords: Krabbe disease; demyelinating disease; oligodendrocyte; psychosine; twitcher mouse