The role of sulfatide in myelin stability

硫脑苷脂在髓磷脂稳定性中的作用

• 批准号: 10373193
• 负责人: Jeffrey L. Dupree
• 金额: $ 19.41万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373193
• 关键词: Adult; Age; Alzheimer' s Disease; Attention; Autoimmune Diseases; Axon; Biochemical; Biological; Brain; Cell Differentiation process; Cell Proliferation; Cell-Cell Adhesion; Complement; Complex; Confocal Microscopy; Consequentialism; Demyelinations; Deterioration; Development; Disease; Disease Progression; Electron Microscopy; Electrons; Electrophysiology (science); Event; Fractionation; Genetic; Glycosphingolipids; Golgi Apparatus; Health; Immunofluorescence Immunologic; Immunologics; Impairment; Lateral; Life; Link; Lipids; Membrane; Methods; Motor; Multiple Sclerosis; Mus; Myelin; Myelin Proteins; Myelin Sheath; Neurodegenerative Disorders; Neurons; Oligodendroglia; Onset of illness; Pathologic; Pathology; Pathway interactions; Play; Proteins; Regulation; Reporting; Role; SNAP receptor; Sensory; Site; Spinal Cord; Structure; Sulfoglycosphingolipids; Techniques; Tertiary Protein Structure; Testing; Vesicle; Work; axonal degeneration; base; cell type; cognitive disability; design; human disease; insight; intercellular communication; myelin degeneration; neuron loss; novel; pre-clinical; protein transport; recruit; trafficking; vesicle transport

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.

概括 多发性硬化症（MS）是一种以CNS脱髓鞘为特征的自身免疫性疾病。 估计表明，MS效应> 70万美国公民。虽然有大约20个批准 疗法，治疗效率有限，无法治愈。 MS的原因未知 但涉及环境，免疫学和遗传因素的相互作用。虽然不 已经建立了遗传联系，研究一致地报告了大幅减少 脱髓鞘之前，髓磷脂脂质硫酸亚硫酸盐。特异性和早期还原硫化物是一致的 随着这种脂质的耗竭，在疾病发作和进展中起着致病的作用。 尽管磺胺的功能尚未完全阐明，但已在A中暗示 各种生物学作用，包括蛋白质运输，细胞 - 细胞粘附，膜 组织，细胞分化和增殖。有趣的是，硫化物的耗竭 还被确定为神经退行性疾病的早期且一致的事件 阿尔茨海默氏病和多发性硬化症。有力的证据表明，在广告中，水平降低 硫化物会损害少突胶质细胞与神经元之间的细胞间通信 在神经元健康中受损。它在多发性硬化症中的作用受到了较少的关注，但是 可能有助于髓磷脂不稳定性和随后的轴突变性。 根据我实验室使用无能力合成亚磺胺的鼠标的工作，看来 这种脂质的耗竭会导致与髓磷脂在MS中观察到的病理学。 但是，我们以前的工作是基于一只在生活的各个阶段缺乏亚磺胺的鼠标 包括早期发展。因此，这些髓磷脂异常可能是 基于亚磺胺违约的发现的适用性异常 小鼠在成人发作疾病方面有些相关。为了克服这一限制，我们 已经产生了一种新的鼠标，使我们能够用细胞类型和年龄特异 规定。使用此鼠标，我们将研究 成年的硫酸亚硫化物损失及其将这些病理学与已知病理相关的MS。 此外，我们建议磺胺在细胞内贩运和MS中起作用，以及我们的 新颖的老鼠，髓磷脂蛋白运输到成熟的髓鞘鞘被妥协导致 髓磷脂完整性的损失。本提案中概述的研究的完成不仅将 提供硫化物的进行性髓磷脂和轴突变性的定量 耗尽，但会研究一种可能在MS中损害的硫化物特异性机制 调节髓磷脂的稳定性和功能。