Impaired myelination in a mouse model of the free sialic acid storage disorders
- Lysosomal storage disorders are inherited diseases caused by defects in lysosomal function. The free sialic acid storage disorders are allelic diseases that are caused by mutations in the gene encoding a lysosomal membrane protein called sialin. This protein transports the acidic sugar, sialic acid, out of lysosomes after it has been cleaved off of glycoconjugates undergoing degradation. Accumulation of sialic acid in lysosomes defines these disorders, but it is not known how this biochemical defect leads to the clinical manifestations. Significant advances in our understanding of the pathophysiology and in treatment have been hindered by the lack of an animal model. In the studies described here I characterize a sialin deficient mouse and provide evidence that it faithfully models important aspects of the human disease. A major finding in the human disease and in the sialin-/- mouse is impaired central nervous system (CNS) myelination. To investigate potential mechanisms underlying CNS hypomyelination, I studied oligodendrocyte development and myelination in optic nerves of the sialin deficient mice. I found reduced numbers of myelinated axons, but the myelin that was present appeared grossly normal. Migration and density of oligodendrocyte precursor cells (OPCs) were normal; however, I observed 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. 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. I hypothesized that improper metabolism of sialic acid containing proteins and lipids (gangliosides) may explain some aspects of the disease phenotype. I found a delay in the developmentally regulated reduction in expression of polysialic acid-neural cell adhesion molecule (PSA-NCAM), a glycoconjugate that inhibits myelin formation, which provides a potential molecular mechanism for the impaired myelination and reduction in oligodendrocyte number. Further, I found elevated levels of gangliosides in the sialin-/- mouse brain with the most noticeable change in the level of ganglioside GM2. To further studies of the myelination defect, I have established a cerebellar slice-OPC coculture myelination assay. This ex vivo system will allow investigators to test specific hypotheses about the cellular and molecular basis of the myelination defect and can eventually be used to assess potential treatments.
|Type of resource
|electronic; electronic resource; remote
|1 online resource.
|Prolo, Laura Marie
|Stanford University, Neurosciences Program.
|Reimer, Richard J
|Reimer, Richard J
|Statement of responsibility
|Laura Marie Prolo.
|Submitted to the Program in Neurosciences.
|Thesis (Ph.D.)--Stanford University, 2012.
- © 2012 by Laura Marie Prolo
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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