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Identification of early neurodegenerative pathways in progressive multiple sclerosis

Item Type:Article
Title:Identification of early neurodegenerative pathways in progressive multiple sclerosis
Creators Name:Kaufmann, M. and Schaupp, A.L. and Sun, R. and Coscia, F. and Dendrou, C.A. and Cortes, A. and Kaur, G. and Evans, H.G. and Mollbrink, A. and Navarro, J.F. and Sonner, J.K. and Mayer, C. and DeLuca, G.C. and Lundeberg, J. and Matthews, P.M. and Attfield, K.E. and Friese, M.A. and Mann, M. and Fugger, L.
Abstract: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.
Keywords:Autoimmunity, Multiple Sclerosis, Neuroimmunology
Source:Nature Neuroscience
ISSN:1097-6256
Publisher:Nature Publishing Group
Volume:25
Number:7
Page Range:944-955
Date:July 2022
Official Publication:https://doi.org/10.1038/s41593-022-01097-3
PubMed:View item in PubMed

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