Progressive leukoencephalopathy impairs neurobehavioral development in sialin-deficient mice

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 developm...

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Published in:	Experimental neurology Vol. 291; pp. 106 - 119
Main Authors:	Stroobants, Stijn, Van Acker, Nathalie G.G., Verheijen, Frans W., Goris, Ilse, Daneels, Guy F.T., Schot, Rachel, Verbeek, Elly, Knaapen, Michiel W.M., De Bondt, An, Göhlmann, Hinrich W., Crauwels, Marion L.A., Mancini, Grazia M.S., Andries, Luc J., Moechars, Dieder W.E., D'Hooge, Rudi
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-05-2017
Subjects:	Age Factors Animals Animals, Newborn Behavior Brain - metabolism Brain - pathology Development Developmental Disabilities - etiology Developmental Disabilities - genetics Disease Models, Animal Gene Expression Regulation, Developmental - genetics Glial Fibrillary Acidic Protein - metabolism Intermediate Filaments - metabolism Leukoencephalopathies - complications Leukoencephalopathies - etiology Leukoencephalopathies - genetics Lysosomal-Associated Membrane Protein 1 - metabolism Mental Disorders - etiology Mice Mice, Inbred C57BL Mice, Transgenic Mouse model Myelination Oligodendrocyte lineage Organic Anion Transporters - deficiency Organic Anion Transporters - genetics Sialic acid storage disease Sialic Acid Storage Disease - complications Sialic Acid Storage Disease - genetics Sialic Acid Storage Disease - pathology Sialin Symporters - deficiency Symporters - genetics dg py Mopb Sialin LAMP-1 PNS Oligodendrocyte lineage icp Development Behavior ec 4V Myrf mt Omg alv Cnp1 ET MEF AR AS Mag Myelination av NG SASD SAM FG fi fl CNS HPS Galc SVZ Pdgfra ISSD MBP Mpeg1 OL RLV CA SR Sialic acid storage disease CC OP vcp cg Cspg4 LD sp5 Mouse model Plp1 PSA-NCAM aca dc
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Summary:	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. •Sialin-deficient mice are a valid model for human sialic acid storage disease.•Sialin-deficient mice show differential gene expression during brain development.•Sialin-deficient mice display specific spatiotemporal defects of CNS myelination.•Aberrant neurobehavioral development parallels their progressive leukoencephalopathy.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0014-4886 1090-2430
DOI:	10.1016/j.expneurol.2017.02.009