title: The lysosomal sialic acid transporter sialin is required for normal CNS myelination.
abstract: Salla disease and infantile sialic acid storage disease are autosomal recessive lysosomal storage disorders caused by mutations in the gene encoding sialin, a membrane protein that transports free sialic acid out of the lysosome after it is cleaved from sialoglycoconjugates undergoing degradation. Accumulation of sialic acid in lysosomes defines these disorders, and the clinical phenotype is characterized by neurodevelopmental defects, including severe CNS hypomyelination. In this study, we used a sialin-deficient mouse to address how loss of sialin leads to the defect in myelination. Behavioral analysis of the sialin(-/-) mouse demonstrates poor coordination, seizures, and premature death. Analysis by histology, electron microscopy, and Western blotting reveals a decrease in myelination of the CNS but normal neuronal cytoarchitecture and normal myelination of the PNS. To investigate potential mechanisms underlying CNS hypomyelination, we studied myelination and oligodendrocyte development in optic nerves. We found reduced numbers of myelinated axons in optic nerves from sialin(-/-) mice, but the myelin that was present appeared grossly normal. Migration and density of oligodendrocyte precursor cells were normal; however, a marked decrease in the number of postmitotic oligodendrocytes and an associated increase in the number of apoptotic cells during the later stages of myelinogenesis were observed. These findings suggest that a defect in maturation of cells in the oligodendrocyte lineage leads to increased apoptosis and underlies the myelination defect associated with sialin loss.
authors.affiliation: Department of Neurology and Neurological Sciences and Graduate Program in Neuroscience, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Prolo
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Reimer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001369:Axons / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D001921:Brain / Q000254:growth & development* / Q000473:pathology / Q000502:physiology*; D002452:Cell Count; D002465:Cell Movement / Q000502:physiology; D008136:Longevity / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D004676:Myelin Basic Protein; D009186:Myelin Sheath / Q000473:pathology / Q000502:physiology* / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D009836:Oligodendroglia / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D009900:Optic Nerve / Q000254:growth & development / Q000473:pathology / Q000648:ultrastructure; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D017933:Peripheral Nervous System / Q000254:growth & development / Q000473:pathology / Q000502:physiology; D012640:Seizures / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000254:growth & development* / Q000473:pathology / Q000502:physiology*; D013234:Stem Cells / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C499047:Mbp protein, mouse; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D027361:Organic Anion Transporters; D027981:Symporters; D014157:Transcription Factors; C421224:sialic acid transport proteins