Axonal Protection by Myelin-Associated Glycoprotein (MAG)

描述(申请人提供)：我们的总体目标是研究脱髓鞘后神经胶质-轴突信号转导机制。虽然脱髓鞘可导致轴突变性已被公认，但这种轴突变性背后的分子机制仍不清楚。由于髓鞘形成细胞(MFC)可以调节轴突的特性，我们推测髓鞘形成通过MFC的轴突质膜上的配体和轴突内轴膜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上关键的MFC配体的丢失有关，从而导致与轴突受体的关键相互作用的丧失。这会导致轴突支持的慢性缺陷，导致迟发性轴突变性，并增加局部炎症介质对轴突丢失的易感性。一个重要的例子是多发性硬化症(MS)，越来越明显的是，中枢神经系统(CNS)的脱髓鞘导致进行性和广泛的轴突丢失，并导致不可逆转的临床缺陷。类似的轴突丧失机制也可能发生在可遗传的人类神经病中，在这些疾病中，髓鞘异常可导致周围神经系统(PNS)的轴突变性。一种神经胶质蛋白，髓鞘相关糖蛋白(MAG)，已知通过轴突神经细丝的磷酸化改变轴突表型。我的初步数据显示，MAG在培养和体内也能促进轴突存活。因此，研究MAG-轴突相互作用的具体目的是：1)建立MAG保护培养神经元免受毒性和炎性损伤的轴突的分析方法；2)表征MAG诱导的信号转导，这是体外轴突存活的基础；3)确认和量化MAG缺失的基因工程小鼠的轴突丢失程度；4)确认特定分子在MFC/轴突信号转导中的作用，这是基因工程和药物治疗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.