Sulfatides Act as Endogenous Toxin Reducing Efficiency of Remyelination

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DESCRIPTION (provided by applicant): Sulfatides, one of the most abundant lipids in myelin sheaths, appear to be released into the extracellular milieu of the brain during myelin destruction in demyelinating diseases such as multiple sclerosis (MS). Because sulfatides have been proposed as negative regulators of oligodendrogenesis, an abnormal elevation of their extracellular levels during demyelinating insult may be one of the factors limiting recovery of myelin by endogenous oligodendrocyte precursors (OPCs). Unfortunately, the mechanism mediating the negative regulation of OPC differentiation by sulfatides is unknown. Preliminary data in this application provides a testable hypothesis stating that sulfatide isoforms released during demyelination exert toxic effects on OPCs by deregulation of the Notch1 and PDGFr¿ signaling pathways. To challenge our hypothesis, we propose experiments to determine the effect of four sulfatide isoforms, C16:0, C18:0, C24:0 and C24:1 (the main isoforms in OPCs and myelin), on the proliferation, cell death- survival, cell cycle, and differentiation capacity o OPCs, by using the well-characterized oligodendrocyte precursor cells isolated from P7 rat corpus callosum. These studies will be performed by immunocytochemical analysis, flow cytometry and liquid chromatography-mass spectrometry of sulfatides from cells grown in the presence of the sulfatide isoforms in proliferating or differentiating conditions. The involvement of Notch1 and PDGFr a receptors will be studied by classical expression experiments and by functional analyses of downstream components in each pathway. Altogether, these studies will allow us to characterize the role of the four sulfatide isoforms in isoforms on OPCs biology, by investigating the functional relevance of two well-studied signaling pathways. The understanding of this process is of fundamental relevance in the design of successful remyelination therapies, which are yet unavailable for those suffering from this demyelinating disease.