Dynamic equilibria of membrane microdomains and protein modifications in central nervous system myelin

髓鞘是包裹在中枢神经系统(CNS)轴突(神经)周围的膜性螺旋，使它们能够有效地传递冲动。髓鞘疾病，如多发性硬化症和Pelizaeus-Merzbacher，会影响中枢神经系统的功能，使人极度虚弱。中枢神经系统髓鞘是由称为少突胶质细胞的细胞膜延伸形成的--一个少突胶质细胞可以包裹几种不同的神经纤维。儿童早期髓鞘的形成是一个复杂的过程，分阶段发生。在每个阶段，必须严格控制基因表达，以产生适量的许多不同成分，然后需要将这些成分输送到细胞中的正确位置。即使在成熟的中枢神经系统中，髓鞘蛋白质和脂类也有持续的周转和补充。当人们在电子显微镜下观察髓鞘时，人们看到的主要是致密的髓鞘，但也有较不致密的环状区域。更仔细的观察表明，髓鞘由不同的“微域”组成，可以通过使用洗涤剂的生化提取来“解剖”出来。这些微域的不同之处不在于它们的组成蛋白质和脂类的组成，而在于这些蛋白质在合成后如何被不同的酶修饰(最后一个过程被称为“翻译后修饰”)。我们的研究旨在了解中枢神经系统髓鞘蛋白的修饰模式在发育过程中如何动态变化，以及在正常成人髓鞘中如何在空间上发生变化。我们观察少突胶质细胞成熟时蛋白质变化的模式，主要是磷酸化和脱胺，因为我们认为这些变化的平衡对维持健康的髓鞘至关重要。作为这项工作的一部分，我们使用各种补充的生化和生物物理技术来研究修饰酶之一(肽基精氨酸脱亚胺酶)和主要组成蛋白(蛋白质脂蛋白)的结构。肽基精氨酸脱亚胺酶是多发性硬化症的一个可能的治疗靶点，潜在的抑制剂应该从功能和结构上进行评估。

The myelin sheath is a membranous spiral that wraps around the axons (nerves) of the central nervous system (CNS), and enables them to transmit impulses efficiently. Diseases of myelin such as multiple sclerosis and Pelizaeus-Merzbacher affect CNS function and are extremely debilitating. The CNS myelin is formed by extensions of membranes of cells called oligodendrocytes - one oligodendrocyte can enwrap several different nerve fibers. The formation of myelin in early childhood is a complex process that occurs in stages. At each stage, gene expression must be strictly controlled to produce the right amounts of many different components that then need to be delivered to the correct location in the cell. Even in the mature CNS, there is constant turnover and replenishment of myelin proteins and lipids. When one looks at myelin in the electron microscope, one sees mainly compact myelin, but also less compact loop regions. An even closer look indicates that myelin consists of different "microdomains" that can be "dissected" out by biochemical extractions with detergents. These microdomains differ not so much in composition of their constituent proteins and lipids, but rather in how these proteins have been modified by different enzymes after synthesis (this last process is called "post-translational modification"). Our research aims to understand how the modification pattern of CNS myelin proteins varies dynamically during development, and spatially in normal adult myelin. We look at the pattern of protein changes as an oligodendrocyte matures, primarily phosphorylation and deimination, because we consider that the balance of these changes is crucial to maintaining a healthy myelin sheath. As part of this endeavour, we look at the structures of one of the modifying enzymes (peptidylarginine deiminase) and of a major constituent protein (proteolipid protein) using a variety of complementary biochemical and biophysical techniques. The peptidylarginine deiminase enzyme represents a possible therapeutic target for multiple sclerosis, and potential inhibitors shall be evaluated functionally and structurally.