The role of sulfatide in myelin stability

摘要 多发性硬化(MS)是一种以中枢神经系统脱髓鞘为特征的自身免疫性疾病。 据估计，多发性硬化症影响了70万美国公民。尽管有~20家已获批准 治疗，治疗的效果有限，而且没有治愈的方法。多发性硬化症病因不明 但涉及环境、免疫和遗传因素的相互作用。虽然不是 基因联系已经建立，研究一致地报告显著减少了 脱髓鞘前的髓磷脂硫脂。硫脂的特异性和早期还原是一致的 这种脂质的耗尽在疾病的发生和发展中起着致病作用。 尽管硫脂的功能尚未完全阐明，但它已被认为与一种 多种生物学作用，包括蛋白质运输、细胞-细胞黏附、膜 组织，以及细胞分化和增殖。有趣的是，硫脂的耗尽 也被确认为神经退行性疾病的早期和持续事件，包括 阿尔茨海默病和多发性硬化症。强有力的证据表明，在AD中， 硫脂损害少突胶质细胞和神经元之间的细胞间通讯 神经健康受损。它在多发性硬化症中的作用受到的关注要少得多，但 可能促进髓鞘不稳定和随后的轴突变性。 根据我的实验室使用一只不能合成硫脂的小鼠所做的工作，似乎 这种脂质的耗尽会导致与MS中观察到的髓鞘缺陷相一致的病理改变。 然而，我们之前的工作是基于一只在生命各个阶段都缺乏硫脂的小鼠 包括早期发展。因此，这些髓鞘异常可能是 发育异常导致硫脂缺乏的研究结果的适用性 关于成年性疾病的小鼠有一些疑问。为了克服这一限制，我们 已经产生了一种新的小鼠，它可以让我们消耗具有特定细胞类型和年龄的硫脂 监管。使用这个鼠标，我们将研究结构和功能后果 成人出现硫脂丢失，并将这些病理与已知的MS病理联系起来。 此外，我们认为硫脂在细胞内转运和多发性硬化症中发挥作用，我们的 新的小鼠，髓鞘蛋白运输到成熟的髓鞘受到损害，导致 髓鞘完整性的丧失。完成这项建议中概述的研究不仅将 提供硫脂引起的进行性髓鞘和轴突变性的定量 消耗，但将研究硫脂的特定机制，这可能是MS的损害， 它调节髓鞘的稳定性和功能。

Summary Multiple sclerosis (MS) is an autoimmune disease characterized by CNS demyelination. Estimates suggest that MS effects >700,000 US citizens. Although there are ~20 approved therapies, treatments have limited efficacies and there is no cure. The cause of MS is unknown but involves an interaction of environmental, immunologic and genetic factors. Although no genetic link has been established, studies consistently report a significant reduction of the myelin lipid sulfatide prior to demyelination. Specific and early reduction of sulfatide is consistent with the depletion of this lipid playing a causative role in disease onset and progression. Although the function of sulfatide has not been fully elucidated, it has been implicated in a variety of biological roles including protein trafficking, cell-cell adhesion, membrane organization, and cell differentiation and proliferation. Interestingly, depletion of sulfatide has also been identified as an early and consistent event in neurodegenerative diseases including Alzheimer’s disease and multiple sclerosis. Strong evidence suggests that in AD reduced levels of sulfatide impairs intercellular communication between oligodendrocytes and neurons resulting in compromised neuronal health. Its role in multiple sclerosis has received far less attention but may facilitate myelin instability and subsequent axonal degeneration. Based on work from my lab using a mouse incapable of synthesizing sulfatide, it appears that depletion of this lipid results in pathologies consistent with myelin deficits observed in MS. However, our previous work was based on a mouse that lacked sulfatide at all stages of life including early development. Therefore, these myelin abnormalities may be consequential of abnormal development rendering the applicability of the findings based on the sulfatide deficient mice somewhat in question with regard to adult onset disease. To overcome this limitation, we have generated a new mouse that allows us to deplete sulfatide with cell type- and age- specific regulation. Using this mouse, we will investigate the structural and functional consequences of adult onset sulfatide loss and relate these pathologies with known pathologies of MS. Additionally, we propose that sulfatide plays a role in intracellular trafficking and in MS, and our novel mouse, myelin protein trafficking to the mature myelin sheath is compromised leading to the loss in myelin integrity. Completion of the studies outlined in this proposal will not only provide quantitation of progressive myelin and axon degeneration consequential of sulfatide depletion but will investigate a sulfatide specific mechanism, that may be compromised in MS, that regulates myelin stability and function.