MS is a common cause of neurological disability. Though there are several effective treatments for the relapsing-remitting form of the disease, many patients either present with primary progressive MS, or eventually progress to secondary progressive MS, for which there are no treatment options. Though pathologically all MS patients have oligodendroglia injury and apoptosis, the pathologic hallmark of progressive MS is axon damage and neuron loss. We have recently characterized a novel function of oligodendroglia-- metabolic support of axons by supplying lactate thru the MCT1 transporter-- and hypothesize that loss of, or injury to, oligodendroglia in MS may produce axon damage through a failure of energy supply via loss of function of this critical oligodendroglial protein. The successful completion of the Aims in this grant will not only further our understanding of axon degeneration in MS, but also provide a potential novel treatment strategy for patients with progressive MS. We hypothesize that reduced expression of MCT1 in injured oligodendroglia of multiple sclerosis patients contributes to axon neurodegeneration and that increasing MCT1 will be protective in the progressive forms of the disease. From a short-term perspective, these studies will provide the foundation of research necessary to determine if this pathway is a viable approach to consider for protecting axons and preventing the chronic neuronal injury that underlies progressive MS. In the long term, independent of this proposal- new innovative approaches toward enhancing this oligodendroglial pathway may provide one day a powerful means to alter long-term neurodegeneration in MS and cortical and motor disability that accompanies neuronal axonal damage in MS.