1. Progressive leukoencephalopathy impairs neurobehavioral development in sialin-deficient mice.
- Author
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Stroobants S, Van Acker NG, Verheijen FW, Goris I, Daneels GF, Schot R, Verbeek E, Knaapen MW, De Bondt A, Göhlmann HW, Crauwels ML, Mancini GM, Andries LJ, Moechars DW, and D'Hooge R
- Subjects
- Age Factors, Animals, Animals, Newborn, Brain metabolism, Developmental Disabilities etiology, Developmental Disabilities genetics, Disease Models, Animal, Glial Fibrillary Acidic Protein metabolism, Intermediate Filaments metabolism, Lysosomal-Associated Membrane Protein 1 metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Organic Anion Transporters genetics, Symporters genetics, Brain pathology, Gene Expression Regulation, Developmental genetics, Leukoencephalopathies complications, Leukoencephalopathies etiology, Leukoencephalopathies genetics, Mental Disorders etiology, Organic Anion Transporters deficiency, Sialic Acid Storage Disease complications, Sialic Acid Storage Disease genetics, Sialic Acid Storage Disease pathology, Symporters deficiency
- Abstract
Slc17a5
-/- mice represent an animal model for the infantile form of sialic acid storage disease (SASD). We analyzed genetic and histological time-course expression of myelin and oligodendrocyte (OL) lineage markers in different parts of the CNS, and related this to postnatal neurobehavioral development in these mice. Sialin-deficient mice display a distinct spatiotemporal pattern of sialic acid storage, CNS hypomyelination and leukoencephalopathy. Whereas few genes are differentially expressed in the perinatal stage (p0), microarray analysis revealed increased differential gene expression in later postnatal stages (p10-p18). This included progressive upregulation of neuroinflammatory genes, as well as continuous down-regulation of genes that encode myelin constituents and typical OL lineage markers. Age-related histopathological analysis indicates that initial myelination occurs normally in hindbrain regions, but progression to more frontal areas is affected in Slc17a5-/- mice. This course of progressive leukoencephalopathy and CNS hypomyelination delays neurobehavioral development in sialin-deficient mice. Slc17a5-/- mice successfully achieve early neurobehavioral milestones, but exhibit progressive delay of later-stage sensory and motor milestones. The present findings may contribute to further understanding of the processes of CNS myelination as well as help to develop therapeutic strategies for SASD and other myelination disorders., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2017
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