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

中枢神经系统髓磷脂膜微区和蛋白质修饰的动态平衡

• 批准号: 121541-2009
• 负责人: Harauz, George
• 金额: $ 2.7万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2010
• 资助国家: 加拿大
• 起止时间: 2010-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=451530
• 关键词: Dynamic; equilibria; membrane; microdomains; protein

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.

髓鞘是一种膜螺旋，包裹在中枢神经系统（CNS）的轴突（神经）周围，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影响CNS功能，并且非常衰弱。中枢神经系统髓鞘是由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个不同的神经纤维。髓鞘在幼儿期的形成是一个复杂的过程，分阶段发生。在每个阶段，基因表达必须严格控制，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，髓鞘蛋白和脂质也不断更新和补充。当我们在电子显微镜下观察髓鞘时，我们看到的主要是致密的髓鞘，但也有不那么致密的环区。更仔细的观察表明，髓磷脂由不同的“微区”组成，可以通过用去污剂进行生化提取而“解剖”出来。这些微结构域的不同之处不在于其组成蛋白质和脂质的组成，而在于这些蛋白质在合成后如何被不同的酶修饰（这最后一个过程被称为“翻译后修饰”）。我们的研究旨在了解CNS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的空间变化。我们研究了少突胶质细胞成熟时蛋白质变化的模式，主要是磷酸化和脱亚氨基化，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。作为这一努力的一部分，我们期待在结构的修饰酶（肽基精氨酸脱亚氨酶）和一个主要组成蛋白质（蛋白脂质蛋白）使用各种互补的生物化学和生物物理技术。肽基精氨酸脱亚胺酶代表了多发性硬化症的一个可能的治疗靶点，潜在的抑制剂应在功能和结构上进行评价。