Proteinopathy in inflammatory neurodegeneration

炎症性神经变性导致多发性硬化症(MS)的残疾进展，多发性硬化症是一种在成年早期出现的无法治愈的虚弱疾病，代表着巨大的健康和社会经济负担。多发性硬化症的一个谜团发现是早期神经元丢失和神经变性的不可避免的进展。然而，关于炎症诱导的神经元改变传播神经元死亡，对MS发病机制的理解存在差距。我们最近对前一个资助期的研究，检查了神经元对炎症的特异性反应谱，发现神经炎症导致小鼠和人类神经元胞体中蛋白质的诱导和有毒沉积。因此，我们提出了一种新的炎性神经变性模型，在该模型中，炎症诱导了神经元反应网络，导致细胞内容易聚集的蛋白质沉积，这些蛋白质扰乱了神经元的生理，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这一模式：1)通过绘制体内发炎神经元的蛋白质组图，并通过表征沉积蛋白质的拓扑网络从而设计出“疾病模块”；2)通过研究易于聚集的蛋白质的炎症驱动活性和溶解性以及它们与蛋白酶体降解途径的相互作用；3)通过鉴定蛋白质是否从细胞间积累扩散到细胞间，并通过探索进行治疗干预的可能性。总体而言，该项目将利用转基因小鼠模型、蛋白质组学、细胞培养和人类组织，系统地揭示神经炎症中的蛋白质病理性疾病模块如何启动、调节和传播神经元退化。它有机会改变MS和其他与神经炎症相关的神经退行性疾病的神经保护性治疗策略的概念方法。

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.