Progressive multiple sclerosis (MS) is characterized by unrelenting neurodegeneration, which causes cumulative disability and is refractory to current treatments. Drug development to prevent disease progression is an urgent clinical need yet is constrained by an incomplete understanding of its complex pathogenesis. Using spatial transcriptomics and proteomics on fresh-frozen human MS brain tissue, we identified multicellular mechanisms of progressive MS pathogenesis and traced their origin in relation to spatially distributed stages of neurodegeneration. By resolving ligand–receptor interactions in local microenvironments, we discovered defunct trophic and anti-inflammatory intercellular communications within areas of early neuronal decline. Proteins associated with neuronal damage in patient samples showed mechanistic concordance with published in vivo knockdown and central nervous system (CNS) disease models, supporting their causal role and value as potential therapeutic targets in progressive MS. Our findings provide a new framework for drug development strategies, rooted in an understanding of the complex cellular and signaling dynamics in human diseased tissue that facilitate this debilitating disease.

进行性多发性硬化症 (MS) 的特征是持续不断的神经变性，这会导致累积性残疾并且对当前治疗难以治愈。预防疾病进展的药物开发是一项紧迫的临床需求，但由于对其复杂发病机制的不完全了解而受到限制。我们对新鲜冷冻的人类 MS 脑组织使用空间转录组学和蛋白质组学，确定了进行性 MS 发病机制的多细胞机制，并追踪了它们与神经变性的空间分布阶段相关的起源。通过解决局部微环境中的配体-受体相互作用，我们发现了早期神经元衰退区域内失效的营养和抗炎细胞间通讯。与患者样本中神经元损伤相关的蛋白质与已发表的体内敲除和中枢神经系统 (CNS) 疾病模型显示出机制一致性，支持它们作为进行性 MS 的潜在治疗靶点的因果作用和价值。我们的研究结果为药物开发策略提供了一个新的框架，其基础是了解人类患病组织中促进这种衰弱性疾病的复杂细胞和信号动力学。