Axonal Protection by Myelin-Associated Glycoprotein (MAG)

描述（由申请人提供）：我们的总体目标是研究神经胶质-轴突信号机制介导脱髓鞘后轴突变性。虽然脱髓鞘可引起轴突变性已被证实，但这种轴突变性的分子机制尚不清楚。由于髓鞘形成细胞（MFC）可以调节轴突特性，我们推测髓鞘形成通过MFC的外轴突质膜中的配体和轴突的轴突内轴突上的受体的相互作用来改变潜在的轴突。脱髓鞘将与轴突质膜中关键MFC配体的丧失有关，从而导致与轴突受体的关键相互作用丧失。这导致轴突支持的慢性缺陷，导致晚发性轴突变性和局部炎症介质对轴突损失的易感性增加。一个重要的例子是多发性硬化症（MS），越来越清楚的是，中枢神经系统（CNS）脱髓鞘导致进行性和广泛的轴突损失，并导致不可逆的临床缺陷。类似的轴突损失机制也可能发生在遗传性人类神经病中，其中髓鞘异常的疾病可导致周围神经系统（PNS）的轴突变性。一种胶质蛋白，髓鞘相关糖蛋白（MAG），已知通过轴突神经丝的磷酸化改变轴突表型。我的初步数据表明，MAG在培养和活体中也能促进轴突的存活。因此，研究mag -轴突相互作用的具体目标是：1)建立MAG对培养神经元的轴突保护实验，2)表征MAG诱导的轴突体外存活的信号，3)确认和量化缺乏MAG的基因工程小鼠轴突损失的程度，4)确认特定分子在MFC/轴突信号中的作用，这是基因工程和药物处理小鼠正常轴突存活的基础。

DESCRIPTION (provided by applicant): 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.