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ToolsMacnair, Will, Calini, Daniela, Agirre, Eneritz, Bryois, Julien, Jäkel, Sarah, Smith, Rebecca Sherrard, Kukanja, Petra, Stokar-Regenscheit, Nadine, Ott, Virginie, Foo, Lynette C., Collin, Ludovic, Schippling, Sven, Urich, Eduard, Nutma, Erik, Marzin, Manuel, Ansaloni, Federico, Amor, Sandra, Magliozzi, Roberta, Heidari, Elyas, Robinson, Mark D., ffrench-Constant, Charles, Castelo-Branco, Gonçalo, Williams, Anna and Malhotra, Dheeraj (2025) snRNA-seq stratifies multiple sclerosis patients into distinct white matter glial responses. Neuron, 113 (3). 396-410.e9. ISSN 0896-6273
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Abstract
Poor understanding of the cellular and molecular basis of clinical and genetic heterogeneity in progressive multiple sclerosis (MS) has hindered the search for new effective therapies. To address this gap, we analyzed 632,000 single-nucleus RNA sequencing profiles from 156 brain tissue samples of MS and control donors to examine inter- and intra-donor heterogeneity. We found distinct cell type-specific gene expression changes between MS gray and white matter, highlighting clear pathology differences. MS lesion subtypes had different cellular compositions but surprisingly similar cell-type gene expression patterns both within and across patients, suggesting global changes. Most gene expression variability was instead explained by patient effects, allowing us to stratify patients and describe the different pathological processes occurring between patient subgroups. Future mapping of these brain molecular profiles with blood and/or CSF profiles from living MS patients will allow precision medicine approaches anchored in patient-specific pathological processes.
| Item Type: | Article |
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| Additional Information: | Data and code availability: • All raw snRNA-seq data (FASTQ files) have been deposited to European Genome-Phenome Archive (EGA),62 as dataset EGA: EGAD00001009169. •The cleaned annotated counts matrices, sample metadata, and cell type annotations for both cohorts are available on Zenodo: https://doi.org/10.5281/zenodo.8338963. •R code and R markdown scripts used to do the analysis in the paper have been deposited at Zenodo: https://doi.org/10.5281/zenodo.8338963. •An interactive web browser to analyze cell type-specific expression levels of genes and transcriptomic changes in MS versus control tissue is available at https://malhotralab.shinyapps.io/MS_broad/ (for broad cell types) and at https://malhotralab.shinyapps.io/MS_fine/ (for fine cell types). •Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. Funding information: A.W. is funded by the MS Society UK, MRC, and the UKDRI (which is funded by the MRC, Alzheimer’s Society, and Alzheimer’s Research UK). G.C.-B. is funded by the Swedish Research Council (2019-01360), the European Union (2020 Research and Innovation Program/European Research Council Consolidator Grant EPIScOPE, 681893), Swedish Brain Foundation (FO2017-0075; FO2018-0162), Ming Wai Lau Centre for Reparative Medicine, Knut and Alice Wallenberg Foundation (grants 2019-0107; 2019-0089), Swedish Society for Medical Research (SSMF, grant JUB2019), the Göran Gustafsson Foundation for Research in Natural Sciences and Medicine, and Karolinska Institutet. E.A. was funded by the European Union, Horizon 2020, Marie-Sklodowska Curie Actions, grant SOLO, number 794689. F.A. was supported by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Resources were funded by F. Hoffmann-La Roche Ltd. Rights retention statement: For the purpose of open access, the authors have applied a Creative Commons Attribution (CC BY) license to any Author Accepted Manuscript version arising from this submission. |
| Uncontrolled Keywords: | demyelination,gray matter,multiple sclerosis,patient stratification,progressive ms,regeneration,remyelination,snrna-seq,white matter,neuroscience(all) ,/dk/atira/pure/subjectarea/asjc/2800 |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 07 Jan 2025 02:18 |
| Last Modified: | 07 Feb 2025 15:30 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/98110 |
| DOI: | 10.1016/j.neuron.2024.11.016 |
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