Chronic low-grade inflammation and neuronal deregulation are two components of a smoldering disease activity that drives the progression of disability in people with multiple sclerosis (MS). Although several therapies exist to dampen the acute inflammation that drives MS relapses, therapeutic options to halt chronic disability progression are a major unmet clinical need. The development of such therapies is hindered by our limited understanding of the neuron-intrinsic determinants of resilience or vulnerability to inflammation. In this Review, we provide a neuron-centric overview of recent advances in deciphering neuronal response patterns that drive the pathology of MS. We describe the inflammatory CNS environment that initiates neurotoxicity by imposing ion imbalance, excitotoxicity and oxidative stress, and by direct neuro-immune interactions, which collectively lead to mitochondrial dysfunction and epigenetic dysregulation. The neuronal demise is further amplified by breakdown of neuronal transport, accumulation of cytosolic proteins and activation of cell death pathways. Continuous neuronal damage perpetuates CNS inflammation by activating surrounding glia cells and by directly exerting toxicity on neighbouring neurons. Further, we explore strategies to overcome neuronal deregulation in MS and compile a selection of neuronal actuators shown to impact neurodegeneration in preclinical studies. We conclude by discussing the therapeutic potential of targeting such neuronal actuators in MS, including some that have already been tested in interventional clinical trials.

慢性低度炎症和神经元失调是闷烧性疾病活动的两个组成部分，可推动多发性硬化症 (MS) 患者的残疾进展。尽管有多种疗法可以抑制导致多发性硬化症复发的急性炎症，但阻止慢性残疾进展的治疗选择是一个未得到满足的主要临床需求。由于我们对炎症恢复力或脆弱性的神经元内在决定因素的有限了解，阻碍了此类疗法的发展。在这篇综述中，我们以神经元为中心概述了破译驱动多发性硬化症病理的神经元反应模式的最新进展。我们描述了炎症性中枢神经系统环境，该环境通过施加离子失衡、兴奋性毒性和氧化应激以及直接的神经免疫相互作用来引发神经毒性，这些相互作用共同导致线粒体功能障碍和表观遗传失调。神经元运输的破坏、胞质蛋白的积累和细胞死亡途径的激活进一步放大了神经元的死亡。持续的神经元损伤通过激活周围的神经胶质细胞并直接对邻近的神经元施加毒性来维持中枢神经系统炎症。此外，我们探索了克服多发性硬化症中神经元失调的策略，并汇编了一系列在临床前研究中显示可影响神经退行性变的神经元执行器。最后，我们讨论了针对多发性硬化症中此类神经元执行器的治疗潜力，其中包括一些已经在介入临床试验中进行过测试的神经元执行器。