Proteinopathy in inflammatory neurodegeneration

炎症性神经变性中的蛋白质病

• 批准号: 321760974
• 负责人: Professor Dr. Manuel A. Friese
• 金额: --
• 依托单位: Institut für Neuroimmunologie und Multiple Sklerose (INIMS)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/321760974?language=en
• 关键词: Proteinopathy; inflammatory; neurodegeneration

Inflammatory neurodegeneration drives disability progression in multiple sclerosis (MS), an incurable and debilitating condition that arises early in adult life and represents an enormous health and socioeconomic burden. An enigmatic finding in MS is the early neuronal loss and inexorable progression of neurodegeneration. However, a gap in understanding MS pathogenesis exists about the inflammatory-induced neuronal alterations that propagate neuronal demise. Our recent study of the previous funding period, examining neuron-specific response profiles in reaction to inflammation, revealed that neuroinflammation leads to the induction and toxic deposition of proteins in neuronal somata in mice and humans. Thus, we propose a novel model for inflammatory neurodegeneration, in which inflammation induces a neuronal response network resulting in intracellular deposition of aggregation-prone proteins that disturb neuronal physiology, spread to adjacent cells and are thereby responsible for progressive neurodegeneration. This study mechanistically explores this model 1) by profiling the proteome of inflamed neurons in vivo and by characterising the topological network of deposited proteins thereby devising a ‘disease module’; 2) by investigating the inflammatory driven activity and solubility of aggregation-prone proteins and their interaction with the proteasome degradation pathway; 3) by identifying whether protein accumulations spread from cell-to-cell and by probing the possibility to therapeutically interfere. Overall, using transgenic mouse models, proteomics, cell culture and human tissue, this project will deliver a systematic unravelment of how neuronal degeneration is initiated, regulated and propagated by a proteinopathic ‘disease module’ in neuroinflammation. It has the chance to change the conceptual approach of neuroprotective treatment strategies in MS and other neurodegenerative diseases associated with neuroinflammation.

炎症性神经变性会导致多发性硬化症 (MS) 的残疾进展，这是一种在成年早期出现的无法治愈且使人衰弱的疾病，带来了巨大的健康和社会经济负担。多发性硬化症的一个神秘发现是早期神经元丢失和神经变性的不可阻挡的进展。然而，对于炎症引起的神经元改变（促进神经元死亡）的理解存在差距。我们最近对上一个资助期的研究检查了对炎症反应的神经元特异性反应谱，结果表明神经炎症会导致小鼠和人类神经元体细胞中蛋白质的诱导和毒性沉积。因此，我们提出了一种炎症性神经变性的新模型，其中炎症诱导神经元反应网络，导致细胞内易于聚集的蛋白质沉积，扰乱神经元生理学，扩散到邻近细胞，从而导致进行性神经变性。本研究从机制上探索了该模型：1）通过分析体内发炎神经元的蛋白质组并表征沉积蛋白质的拓扑网络，从而设计出“疾病模块”； 2) 通过研究易聚集蛋白的炎症驱动活性和溶解度及其与蛋白酶体降解途径的相互作用； 3）通过确定蛋白质积累是否在细胞间扩散并探讨治疗干扰的可能性。总体而言，该项目将利用转基因小鼠模型、蛋白质组学、细胞培养和人体组织，系统地揭示神经炎症中蛋白质病理“疾病模块”如何引发、调节和传播神经元变性。它有机会改变多发性硬化症和其他与神经炎症相关的神经退行性疾病的神经保护治疗策略的概念方法。