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

少突胶质细胞的主要功能是产生髓鞘，促进动作电位的传导，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和随后的脱髓鞘和轴突变性是多发性硬化症（MS）的标志。究竟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尚不清楚，尤其是在进行性多发性硬化症中。未折叠蛋白反应（UPR）是一种众所周知的恢复细胞稳态的信号通路。虽然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，目前尚不清楚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，因此，神经退行性变，特别是在MS的进展阶段，这是目前难以治疗的。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。不出所料，在多发性硬化症病变中，包括少突胶质细胞在内的几种细胞类型中报道了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，并将其与来自人类MS样本的特征进行比较。我们将利用MS的非炎性（铜酮）和T细胞主导的实验性自身免疫性脑脊髓炎（EAE）模型（MOG-EAE），它们适合研究个体和确定的发病机制（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，在进行性MS模型中，DDIT3在少突胶质细胞中特异性表达，并且DDIT3缺陷小鼠的少突胶质细胞免于凋亡。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之间的联系。我们将补充标准方法与基于设计的立体学定量少突胶质细胞保存。为了进一步了解将UPR激活与少突胶质细胞死亡联系起来的复杂信号级联，我们将使用原代少突胶质细胞培养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开发保护进展性多发性硬化症少突胶质细胞和神经元的治疗策略提供基础。

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.