Activation of the unfolded protein response in multiple sclerosis: Relevance for lesion development and progression

多发性硬化症中未折叠蛋白反应的激活：与病变发生和进展的相关性

• 批准号: 398138584
• 负责人: Professor Dr. Markus Kipp
• 金额: --
• 依托单位: Institut für Anatomie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/398138584?language=en
• 关键词: Activation; unfolded; protein; response; multiple

The primary functions of oligodendrocytes are to produce the myelin sheath, which hastens the conduction of action potential and protects axons from inflammatory environments, and to provide nutritional support to axons. The death of oligodendrocytes and the subsequent demyelination and axonal degeneration are hallmarks of multiple sclerosis (MS). What kills the oligodendrocytes and to what extent this is linked to axonal degeneration are not well understood, especially during progressive MS. The unfolded protein response (UPR) represents a signaling pathway well known for restoring cellular homeostasis. Although UPR activation can aid cells in adapting to stress, it can also trigger apoptosis. However, it is not known how the UPR selects between cytoprotective and proapoptotic outputs. Such mechanisms may regulate oligodendrocyte pathology and, in consequence, neurodegeneration, especially during the progressive stage of MS, which is currently refractory to any therapy. There is accumulating evidence that inflammatory mediators as well as metabolic disturbances also activate the UPR, which was originally described as triggered by misfolded proteins. Not surprisingly, UPR activation was reported in several cell types in MS lesions, including oligodendrocytes. Of note, oligodendrocytes are highly sensitive to activation of the UPR, which has unique features in these cells. We will first phenotype the UPR signatures in different MS animal models and compare them to the signature from human MS samples. We will utilize noninflammatory (cuprizone) and T cell-dominated experimental autoimmune encephalomyelitis (EAE) models (MOG-EAE) of MS, which are suited for studying individual and defined pathogenetic mechanisms (i.e., metabolic- versus immune-mediated oligodendrocyte degeneration). Second, we will focus on the functional role of the UPR transcription factor DNA damage-inducible transcript 3 (DDIT3). Our preliminary results show that DDIT3 is specifically expressed by oligodendrocytes in a progressive MS model, and oligodendrocytes in Ddit3-deficient mice are protected from apoptosis. This study aims to understand how inflammation, UPR activation, oligodendrocyte loss, and axonal pathology are linked. We will complement standard methods with design-based stereology for quantifying oligodendrocyte preservation. To further understand the complex signaling cascade linking UPR activation with oligodendrocyte death, we will perform mechanistic studies using primary oligodendrocyte cultures and suitable cell lines. The knowledge gained from these studies will provide a foundation for developing therapeutic strategies that protect oligodendrocytes and neurons in progressive MS.

少突胶质细胞的主要功能是产生髓鞘，加速动作电位的传导并保护轴突免受炎症环境的影响，并为轴突提供营养支持。少突胶质细胞的死亡以及随后的脱髓鞘和轴突变性是多发性硬化症（MS）的标志。是什么杀死了少突胶质细胞，以及这在多大程度上与轴突变性有关，目前尚不清楚，特别是在进行性多发性硬化症期间。 未折叠蛋白反应（UPR）代表了众所周知的恢复细胞稳态的信号通路。尽管UPR激活可以帮助细胞适应压力，但它也可以引发细胞凋亡。然而，尚不清楚 UPR 如何在细胞保护和促凋亡输出之间进行选择。这种机制可能调节少突胶质细胞病理学，从而调节神经变性，特别是在多发性硬化症的进展阶段，目前任何治疗都难以治愈。越来越多的证据表明，炎症介质和代谢紊乱也会激活 UPR，而 UPR 最初被描述为由错误折叠的蛋白质触发。毫不奇怪，据报道，多发性硬化症病变中的几种细胞类型（包括少突胶质细胞）中都有 UPR 激活。值得注意的是，少突胶质细胞对 UPR 的激活高度敏感，UPR 在这些细胞中具有独特的特征。 我们将首先对不同 MS 动物模型中的 UPR 特征进行表型分析，并将其与人类 MS 样本的特征进行比较。我们将利用多发性硬化症的非炎症（铜宗）和 T 细胞主导的实验性自身免疫性脑脊髓炎 (EAE) 模型 (MOG-EAE)，该模型适合研究个体和明确的发病机制（即代谢与免疫介导的少突胶质细胞变性）。其次，我们将重点关注 UPR 转录因子 DNA 损伤诱导转录物 3 (DDIT3) 的功能作用。我们的初步结果表明，DDIT3 在进行性 MS 模型中由少突胶质细胞特异性表达，并且 Ddit3 缺陷小鼠中的少突胶质细胞受到保护免于凋亡。本研究旨在了解炎症、UPR 激活、少突胶质细胞丢失和轴突病理学之间的关系。我们将用基于设计的体视学来补充标准方法，以量化少突胶质细胞的保存。为了进一步了解连接 UPR 激活与少突胶质细胞死亡的复杂信号级联，我们将使用原代少突胶质细胞培养物和合适的细胞系进行机制研究。 从这些研究中获得的知识将为制定保护进行性多发性硬化症中少突胶质细胞和神经元的治疗策略奠定基础。