: Myelination is an essential and critical process for normal neurological development While Schwann cells of the peripheral nervous system (PNS) exhibit greater plasticity and facility in remyelination to repair damage, oligodendrocytes of the central nervous system (CNS) undergo terminal differentiation and display far more limited capacity to replace myelin that is lost due to disease or trauma. As compared to the PNS where a Schwann cell myelinates a single internode, myelin loss in the CNS is more catastrophic because a single oligodendrocyte may ensheath up to 50 internodes. Multiple sclerosis, an immune-mediated demyelinating disease, is probably the most prominent disease in which CNS myelin is specifically targeted for destruction by the immune system. While drugs have been developed to slow disease progression, MS is a progressive and, ultimately, fatal disease process. Oligodendrocytes elaborate tremendous amounts of plasma membrane during early vertebrate development, and the composition of this membrane differs greatly from that of the oligodendroglial cell body or its processes. Myelin/oligodendrocyte glycoprotein (MOG) is a major target antigen involved in immune-mediated demyelination and is localized to uncompacted membrane surfaces of oligodendrocytes. We are studying potential interactions been MOG's cytoplasmic domains and intracellular components of oligodendrocytes. Our studies have evolved to determine how MOG is targeted to specific membrane domains, and as correlative work, we will begin an analysis of how proteolipid protein (PLP) targets to compact myelin membrane. This application is designed to use MOG and PLP as models that will provide contrasting aspects in how oligodendroglial proteins are delivered to different cellular compartments.
In Specific Aim #1, we will define what determinants within MOG's cytoplasmic domain direct its membrane targeting and what intracellular molecules interact with these domains.
In Specific Aim #2, we will use homologous recombination to generate mice expressing a truncated form of MOG that will lack its targeting elements. Finally, the work in Specific Aim #3 will investigate how different products of the PLP gene are targeted to different membrane compartments; in this case, we will study both normal and naturally occurring mutant gene products. Via yeast two hybrid and co-immunoprecipitation strategies, the outcome of these experiments will identify potential interaction partners that are involved in the sorting and vesicular trafficking of MOG and PLP. Because these proteins sort to distinctly different locations, we should obtain new information regarding both pathways used by oligodendrocytes.
| Kroepfl, J F; Gardinier, M V (2001) Identification of a basolateral membrane targeting signal within the cytoplasmic domain of myelin/oligodendrocyte glycoprotein. J Neurochem 77:1301-9 |
| Kroepfl, J F; Gardinier, M V (2001) Mutually exclusive apicobasolateral sorting of two oligodendroglial membrane proteins, proteolipid protein and myelin/oligodendrocyte glycoprotein, in Madin-Darby canine kidney cells. J Neurosci Res 66:1140-8 |
