Identification of early neurodegenerative pathways in progressive multiple sclerosis

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 CNS disease models, supporting their causal role and value as potential therapeutic targets for 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. Overall design: Spatial transcriptomics of fresh frozen cortical brain tissue from 32 MS sections and 5 control sections. NOTE: The following files were updated (on Aug 23, 2022) to the most recent version that exactly matches the data needed to reproduce the study's findings: GSE174647_ST_counts.tar.gz GSE174647_ST_spatial_coord_annotations_spots.csv.gz The following files have been added to the records (on Nov 24, 2023): GSE174647_code.tar.gz: This code assists users in working with the data and ensures full reproducibility of our original analysis. GSE174647_code_accompanying_data.tar.gz: This includes processed data accompanying the code, ensuring that each script can run independently without needing to execute the entire analysis. GSE174647_tissue_block_identification.pdf: This document offers a detailed explanation of the nomenclature used for identifying each tissue block in the brain, complete with images of reference brain sections for enhanced understanding. The following files were updated (on Nov 24, 2023) for compatibility with the code: GSE174647_ST_spatial_coord_annotations_spots.csv.gz GSE174647_ST_tissue_images.tar.gz

进行性多发性硬化症（multiple sclerosis，简称MS）以持续性神经退变为核心特征，可引发累积性残疾，且现有治疗方案对此无效。开发可阻断疾病进展的药物是临床亟待满足的需求，但目前因对其复杂发病机制的认知尚不充分而受到极大限制。
本研究针对新鲜冷冻的人类MS脑组织样本，采用空间转录组学（spatial transcriptomics）与蛋白质组学（proteomics）技术，解析了进行性MS发病的多细胞机制，并追溯了这些机制与空间分布的神经退变阶段的关联。
通过解析局部微环境中的配体-受体相互作用，我们在早期神经元衰退区域发现了功能失常的营养支持与抗炎细胞间通讯通路。
患者样本中与神经元损伤相关的蛋白质，其作用机制与已发表的体内敲低模型及中枢神经系统（Central Nervous System, CNS）疾病模型具有高度一致性，这证实了这些蛋白的因果作用及其作为进行性MS潜在治疗靶点的价值。
本研究的发现为药物开发策略提供了全新的理论框架，该框架植根于对人类病变组织中复杂细胞与信号动态的精准认知，有望为攻克这一致残性疾病提供新的路径。
总体实验设计：对32例MS脑组织切片及5例对照脑组织切片的新鲜冷冻皮层脑组织进行空间转录组学检测。
注意事项：
下述文件已于2022年8月23日更新至与本研究结果复现所需数据完全匹配的最新版本：GSE174647_ST_counts.tar.gz、GSE174647_ST_spatial_coord_annotations_spots.csv.gz。
下述文件于2023年11月24日新增至数据集记录中：
GSE174647_code.tar.gz：该代码可协助用户处理本数据集，并确保本研究原始分析的完全可复现。
GSE174647_code_accompanying_data.tar.gz：该压缩包包含与代码配套的处理后数据，可确保每个脚本独立运行，无需执行完整分析流程。
GSE174647_tissue_block_identification.pdf：该文档详细阐释了用于识别脑内各组织块的命名规则，并配有参考脑组织切片图像以辅助理解。
下述文件于2023年11月24日更新以适配代码兼容性：GSE174647_ST_spatial_coord_annotations_spots.csv.gz、GSE174647_ST_tissue_images.tar.gz