snRNA-seq stratifies multiple sclerosis patients into distinct white matter glial responses
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.
Authors
- Erik Nutma (ORCID: https://orcid.org/0000-0002-7332-1636)
- Eneritz Agirre (ORCID: https://orcid.org/0000-0002-5012-0305)
- Rebecca Sherrard Smith (ORCID: https://orcid.org/0009-0000-7216-0706)
- Eduard Urich (ORCID: https://orcid.org/0000-0003-0238-5517)
- Charles ffrench‐Constant (ORCID: https://orcid.org/0000-0002-5621-3377)
- Petra Kukanja (ORCID: https://orcid.org/0000-0003-1228-5923)
- Daniela Calini
- Mark D. Robinson (ORCID: https://orcid.org/0000-0002-3048-5518)
- Lynette C. Foo (ORCID: https://orcid.org/0000-0001-6351-8374)
- Will Macnair (ORCID: https://orcid.org/0000-0001-6357-0834)
- Sandra Amor (ORCID: https://orcid.org/0000-0001-6169-9845)
- Gonçalo Castelo‐Branco (ORCID: https://orcid.org/0000-0003-2247-9393)
- Federico Ansaloni (ORCID: https://orcid.org/0000-0002-6344-4931)
- Ludovic Collin (ORCID: https://orcid.org/0000-0002-6313-3244)
- Elyas Heidari (ORCID: https://orcid.org/0000-0002-6004-3999)
- Anna Williams (ORCID: https://orcid.org/0000-0002-6329-382X)
- Roberta Magliozzi (ORCID: https://orcid.org/0000-0001-8284-7763)
- Nadine Stokar‐Regenscheit (ORCID: https://orcid.org/0000-0003-4089-2026)
- Virginie Ott
- Manuel Marzin
- Julien Bryois (ORCID: https://orcid.org/0000-0002-4747-2166)
- Sven Schippling (ORCID: https://orcid.org/0000-0002-6804-1795)
- Sarah Jäkel (ORCID: https://orcid.org/0000-0002-9634-2472)
- Dheeraj Malhotra (ORCID: https://orcid.org/0000-0003-4700-4407)
Institutions
- University of East Anglia (GB)
- Roche (Switzerland) (CH)
- University of Verona (IT)
- SIB Swiss Institute of Bioinformatics (CH)
- University of Zurich (CH)
- Biomedical Primate Research Centre (NL)
- Karolinska Institutet (SE)
- MRC Centre for Regenerative Medicine (GB)
- Munich Cluster for Systems Neurology (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Neuron
- Published
- 2024-12-20
- DOI
- https://doi.org/10.1016/j.neuron.2024.11.016
- Citations
- 37
- Primary Topic
- RNA regulation and disease
- Type
- article
- Field-Weighted Citation Impact
- 8.42
Funders
- F. Hoffmann-La Roche
- European Committee for Treatment and Research in Multiple Sclerosis
- Alzheimer's Society
- Multiple Sclerosis Society
- European Commission
- Svenska Forskningsrådet Formas
- Svenska Sällskapet för Medicinsk Forskning
- Karolinska Institutet
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Universität Zürich
- Swedish Brain Power
- UK Dementia Research Institute
- Medical Research Council
- European Research Council
- Functional Genomics Center Zurich
- HORIZON EUROPE Marie Sklodowska-Curie Actions