Identification of early neurodegenerative pathways in progressive multiple sclerosis
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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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature Neuroscience |
| Vol/bind | 25 |
| Sider (fra-til) | 944-955 |
| ISSN | 1097-6256 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
G.C.D. has received research funding from Merck Serono, travel expenses from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis and honoraria as an invited speaker/faculty/advisor for Novartis and Roche. J.L. and A.M. are scientific consultants for 10X Genomics. P.M.M. has received consultancy fees from Roche, Adelphi Communications, Celgene, Neurodiem and Medscape, honoraria or speakers’ fees from Novartis and Biogen and has received research or educational funds from Biogen, Novartis and GlaxoSmithKline. The remaining authors declare no competing interests.
Funding Information:
We thank M. Esiri (University of Oxford) for advice and assistance in characterization of postmortem brain tissue, and G. McVean (Big Data Institute, University of Oxford) for analytical support. M.K. is supported by an MS Clinician-Scientist Fellowship from Stifterverband für die Deutsche Wissenschaft and by a Walter-Benjamin-Fellowship from Deutsche Forschungsgemeinschaft (nos. KA5554/1-1 and KA5554/1-2). F.C. is supported by the European Union’s Horizon 2020 research and innovation program under grant agreement no. 846795 (Marie Skłodowska-Curie Fellowship). P.M.M. is supported by the Edmond J. Safra Foundation and Lily Safra, an NIHR Senior Investigator Award and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. M.A.F. is supported by intramural funds of the University Medical Center Hamburg-Eppendorf, Deutsche Forschungsgemeinschaft (nos. SFB1328, SPP1738, KFO296, FOR2289, FOR2879, FOR5068 and FR1720/11-2), Gemeinnützige Hertie-Stiftung, Deutsche Multiple Sklerose Gesellschaft (no. V6.2) and Bundesministerium für Bildung und Forschung (Target validation, no. 16GW0308K). M.M. is supported by the Max Planck Society for the Advancement of Science, the Novo Nordisk Foundation (grant agreement nos. NNF14CC0001 and NNF15CC0001) and the European Union’s Horizon 2020 research and innovation program under grant agreement no. 686547 (MSmed Project). L.F. is supported by Wellcome (no. 100308/Z/12/Z), Medical Research Council UK (no. MC_UU_12010/3), the Oak Foundation (no. OCAY-15-520) and NIHR Oxford BRC.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
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