Our overall objective is to investigate the glia-axonal signaling mechanism mediating axonal degeneration after demyelination. While it is well established that demyelination can cause axonal degeneration, the molecular mechanism underlying this axonal degeneration remains unclear. Since myelin-forming cells (MFC's) can modulate axonal properties, we speculate that myelination alters the underlying axon by interaction of ligands in the adaxonal plasmalemma of MFC's and receptors on the intenodal axolemma of the axons. Demyelination will be associated with loss of critical MFC ligands in the adaxonal plasmalemma with consequent loss of the critical interaction with the axonal receptor. This results in chronic defect in axonal support, leading to late onset axonal degeneration and increased susceptibility to axonal loss by local inflammatory mediators. One important example is multiple sclerosis (MS), where it is increasingly clear that demyelination of the central nervous system (CNS) results in progressive and extensive axonal loss and contributes to irreversible clinical deficits. A similar mechanism of axonal loss may also occur in the heritable human neuropathies, in which disorders with abnormalities of myelin can lead to axonal degeneration in the peripheral nervous system (PNS). One glial protein, the myelin-associated glycoprotein (MAG), is known to alter axonal phenotype through phosphorylation of axonal neurofilaments. My preliminary data show that MAG also promotes axonal survival in culture and in vivo. Hence, the Specific Aims for the proposed studies to examine MAG-axonal interactions are: 1) to establish assays for axonal protection by MAG from toxic and inflammatory insults in cultured neurons, 2) to characterize the MAG-induced signaling that underlies the axonal survival in vitro, 3) to confirm and quantitate the degree for axonal loss in genetically engineered mice lacking MAG, and 4) to confirm the role of specific molecules in the MFC/axonal signaling that underlies the normal axonal survival in genetically engineered and pharmacologically treated mice. ? ? ?
| Ewaleifoh, Osefame; Trinh, Minh; Griffin, John W et al. (2012) A novel system to accelerate the progression of nerve degeneration in transgenic mouse models of neuropathies. Exp Neurol 237:153-9 |
| Nguyen, Thien; Mehta, Niraj R; Conant, Katherine et al. (2009) Axonal protective effects of the myelin-associated glycoprotein. J Neurosci 29:630-7 |
