The role of sulfatide in myelin stability

总结 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，MS影响超过70万美国公民。虽然有~20个批准 治疗，治疗的效果有限，没有治愈的方法。MS的病因不明 但涉及环境、免疫和遗传因素的相互作用。虽然没有 遗传联系已经建立，研究一致报告， 髓鞘脂质硫脂在脱髓鞘之前。特异性和早期减少硫苷脂是一致的 这种脂质的消耗在疾病的发生和发展中起着致病作用。 虽然硫苷脂的功能尚未完全阐明，但它已被牵连到一个 多种生物学作用，包括蛋白质运输、细胞-细胞粘附、膜 组织和细胞分化和增殖。有趣的是，硫苷脂的消耗 也被确定为神经退行性疾病的早期和一致事件，包括 老年痴呆症和多发性硬化症。强有力的证据表明，在AD中， 硫苷脂损害少突胶质细胞和神经元之间的细胞间通讯， 神经系统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， 可能促进髓鞘不稳定和随后的轴突变性。 基于我的实验室使用不能合成硫苷脂的老鼠的工作， 这种脂质的消耗导致与MS中观察到的髓鞘缺乏一致的病理。 然而，我们之前的工作是基于一只在生命的各个阶段都缺乏硫苷脂的老鼠 包括早期发展。因此，这些髓鞘异常可能是 异常发育使得基于硫苷脂缺乏的研究结果适用 小鼠在成年发病方面有些问题。为了克服这一局限性，我们 已经培育出一种新的小鼠，使我们能够用特定细胞类型和年龄来消耗硫苷脂。 调控使用这种小鼠，我们将研究结构和功能的后果， 成人发病硫苷脂损失，并将这些病理与MS的已知病理联系起来。 此外，我们认为硫苷脂在细胞内运输和MS中起作用， 一种新的小鼠，髓鞘蛋白运输到成熟的髓鞘是受损的，导致 髓鞘完整性的丧失。完成本建议中概述的研究不仅将 提供硫苷脂引起的进行性髓鞘和轴突变性的定量 消耗，但将研究硫苷脂的具体机制，这可能是妥协的MS， 调节髓磷脂稳定性和功能。

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.