The role of sulfatide in myelin stability - Summary Multiple sclerosis (MS) is an autoimmune disease characterized by CNS demyelination. Estimates suggest that MS effects >700,000 US citizens. Although there are ~20 approved therapies, treatments have limited efficacies and there is no cure. The cause of MS is unknown but involves an interaction of environmental, immunologic and genetic factors. Although no genetic link has been established, studies consistently report a significant reduction of the myelin lipid sulfatide prior to demyelination. Specific and early reduction of sulfatide is consistent with the depletion of this lipid playing a causative role in disease onset and progression. Although the function of sulfatide has not been fully elucidated, it has been implicated in a variety of biological roles including protein trafficking, cell-cell adhesion, membrane organization, and cell differentiation and proliferation. Interestingly, depletion of sulfatide has also been identified as an early and consistent event in neurodegenerative diseases including Alzheimer’s disease and multiple sclerosis. Strong evidence suggests that in AD reduced levels of sulfatide impairs intercellular communication between oligodendrocytes and neurons resulting in compromised neuronal health. Its role in multiple sclerosis has received far less attention but may facilitate myelin instability and subsequent axonal degeneration. Based on work from my lab using a mouse incapable of synthesizing sulfatide, it appears that depletion of this lipid results in pathologies consistent with myelin deficits observed in MS. However, our previous work was based on a mouse that lacked sulfatide at all stages of life including early development. Therefore, these myelin abnormalities may be consequential of abnormal development rendering the applicability of the findings based on the sulfatide deficient mice somewhat in question with regard to adult onset disease. To overcome this limitation, we have generated a new mouse that allows us to deplete sulfatide with cell type- and age- specific regulation. Using this mouse, we will investigate the structural and functional consequences of adult onset sulfatide loss and relate these pathologies with known pathologies of MS. Additionally, we propose that sulfatide plays a role in intracellular trafficking and in MS, and our novel mouse, myelin protein trafficking to the mature myelin sheath is compromised leading to the loss in myelin integrity. Completion of the studies outlined in this proposal will not only provide quantitation of progressive myelin and axon degeneration consequential of sulfatide depletion but will investigate a sulfatide specific mechanism, that may be compromised in MS, that regulates myelin stability and function.
