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. 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