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MYELIN ASSEMBLY AND ITS GENETIC DISORDER

髓磷脂组装及其遗传疾病

基本信息

批准号：
3394691
负责人：
EDWARD L. HOGAN
金额：
$ 11.56万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
1976
资助国家：
美国
起止时间：
1976-05-01 至 1990-11-30
项目状态：
已结题

项目摘要

These studies examine myelin assembly employing designs directed at intracellular processing of two integral proteins, proteolipid protein (PLP) and myelin associated glycoprotein (MAG). We will use an in vitro system of tissue slices prepared from actively myelinating murine brainstem. Different labeling protocols and specific inhibitors will be used to delineate the intracellular itinerary and the sites of co- and posttranslational modifications, specifically acylation of PLP and glycosylation of MAG. The kinetics of passage through different subcellular organelles (half-lifes and turn-over rates) will reveal whether PLP and MAG follow the same or different intracellular pathways, and whether the same or different mechanisms regulate their intracellular transport. We will employ specific inhibitors of protein glycosylation to block processing of MAG at different stages in order to determine the role of the oligosaccharide moiety in the sorting and trafficking of proteins. The dysmyelinating mouse mutant quaking which is characterized by genetic underexpression of 72p MAG and overexpression of 67p MAG polypeptides, and their abnormal glycosylation will be a useful biological probe to study the regulatory role of MAG in myelinogenesis. The aberrant MAG metabolism may be the primary disorder in quaking. We will study co- and posttranslational processing of MAG polypeptides in cellular organelles to gain insight into their metabolic relationship(s) during assembly. In addition, we will explore the possibility that the primary structure of MAG polypeptides are altered in quaking. We believe that these studies will lead to new concepts regarding the biochemical events controlling myelination. Once the mechanisms of myelin sheath formation are understood, therapies can be developed to potentiate remyelination in such diseases as multiple sclerosis.

这些研究采用针对以下目的的设计来检查髓磷脂组装：细胞内两种主要蛋白质的加工，蛋白脂质蛋白 (PLP)和髓磷脂相关糖蛋白（MAG）。我们将使用体外从活跃髓鞘形成的鼠制备的组织切片系统脑干不同的标记方案和特异性抑制剂将被使用。用于描绘细胞内行程和共同和翻译后修饰，特别是PLP的酰化， MAG的糖基化。亚细胞器（半衰期和周转率）将揭示是否 PLP和MAG遵循相同或不同的细胞内途径，并且是否有相同或不同的机制调节它们的细胞内运输我们将使用蛋白质糖基化的特异性抑制剂，以确定MAG在不同阶段的作用在蛋白质的分类和运输中的寡糖部分。髓鞘发育障碍小鼠突变体震颤，其特征在于遗传性 72p MAG的低表达和67p MAG多肽的过表达，和它们的异常糖基化将是研究糖基化的一个有用的生物探针。 MAG在髓鞘形成中的调节作用。异常的MAG代谢可能是地震的主要障碍。我们将共同学习， MAG多肽在细胞器中的翻译后加工，了解它们在组装过程中的代谢关系。在此外，我们将探讨MAG的一级结构的可能性，多肽在震动中改变。我们认为，这些研究将导致有关控制髓鞘形成的生化事件。一旦髓磷脂的机制了解鞘形成，可以开发治疗以增强在多发性硬化症等疾病中的髓鞘再生。