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Neuronal vulnerability and multilineage diversity in multiple sclerosis
Open accessAbstract
Multiple sclerosis (MS) is a neuroinflammatory disease with a relapsing-remitting disease course at early stages, distinct lesion characteristics in cortical grey versus subcortical white matter and neurodegeneration at chronic stages. Here we used single-nucleus RNA sequencing to assess changes in expression in multiple cell lineages in MS lesions and validated the results using multiplex in situ hybridization. We found selective vulnerability and loss of excitatory CUX2-expressing projection neurons in upper-cortical layers underlying meningeal inflammation; such MS neuron populations exhibited upregulation of stress pathway genes and long non-coding RNAs. Signatures of stressed oligodendrocytes, reactive astrocytes and activated microglia mapped most strongly to the rim of MS plaques. Notably, single-nucleus RNA sequencing identified phagocytosing microglia and/or macrophages by their ingestion and perinuclear import of myelin transcripts, confirmed by functional mouse and human culture assays. Our findings indicate lineage- and region-specific transcriptomic changes associated with selective cortical neuron damage and glial activation contributing to progression of MS lesions.
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“It is well established that focal lesions such as those in the brainstem result in axonal loss, and that cortical demyelination, which occurs independently of white matter lesions, is associated with selective neuronal loss18; both these degenerative features are prominent determinants of progression18,19.”
From Locus for severity implicates CNS resilience in progression of multiple sclerosis (2023) · cites this paper as [18]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Besides these clinical differences, homozygous rs10191329 risk allele carriers also demonstrated more severe MS-specific brainstem and cortical pathology, which result in axonal and neuronal degeneration respectively and drive progression18,19.”
From Locus for severity implicates CNS resilience in progression of multiple sclerosis (2023) · cites this paper as [18]
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“This cluster was selectively enriched within acute/chronic active MS lesions (Fig. 4 C and D and Dataset S7).”
From Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination (2025) · cites this paper as [37]
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“Together, these results suggest microglia contribute to both the development and progression of MS”
From Activated microglia drive demyelination via CSF1R signaling (2021) · cites this paper as Schirmer et al., 2019
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“A reanalysis of the human MS snRNA-seq dataset from Schirmer et al. (37) showed that microglia coexpressed TREM2 and MAFB (SI Appendix, Fig. S9 A–D).”
From Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination (2025) · cites this paper as [37]
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“Reclustering of microglia revealed three distinct clusters spanning three different MS conditions (Fig. 4 A and B and Dataset S7).”
From Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination (2025) · cites this paper as [37]
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“MS lesions, particularly the rims of chronic active lesions, contain stressed OLs, reactive astrocytes, and activated phagocytosing microglia/macrophages11,12,15.”
From A comparative transcriptomic analysis of mouse demyelination models and multiple sclerosis lesions (2026) · cites this paper as [12]
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“Interestingly, B2M was not significantly upregulated by MOLs in any MS lesion type, however it has been shown to be upregulated in other MS datasets11–13.”
From A comparative transcriptomic analysis of mouse demyelination models and multiple sclerosis lesions (2026) · cites this paper as [12]
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“As tools for identifying and visualizing microglia have advanced, numerous studies have found reactive microglia in both active, and pre-active MS lesions (Lassmann, 2014; van der Valk & Amor, 2009; Zhang et al., 2011), including evidence for their active phagocytosis of myelin and myelin transcripts (Schirmer et al., 2019).”
From Activated microglia drive demyelination via CSF1R signaling (2021) · cites this paper as Schirmer et al., 2019
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“In this dataset, MAFB was also weakly expressed in inhibitory neurons.”
From Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination (2025) · cites this paper as [37]
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“Within these clusters, cluster 1 stood out due to its pronounced MAFB expression.”
From Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination (2025) · cites this paper as [37]
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“The ground truth cell-type labels were taken from the original publication of the data [19].”
From A Deep Dive into Single-Cell RNA Sequencing Foundation Models (2023) · cites this paper as [19]
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Metadata
- Authors
- Schirmer, L., Velmeshev, D., Holmqvist, S., Kaufmann, M., Werneburg, S., Jung, D., Vistnes, S., Stockley, J. H., Young, A., Steindel, M., Tung, B., Goyal, N., Bhaduri, A., Mayer, S., Engler, J. B., Bayraktar, O. A., Franklin, R. J. M., Haeussler, M., Reynolds, R., Schafer, D. P., Friese, M. A., Shiow, L. R., Kriegstein, A. R., & Rowitch, D. H.
- Affiliations
- University of California, San Francisco (US)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Universität Hamburg (DE)
- University of Massachusetts Chan Medical School (US)
- University of California, Santa Cruz (US)
- Imperial College London (GB)
- Corresponding author
- Kriegstein, Arnold R.
- Rowitch, David H.
- ORCID
- Schirmer, Lucas
- Velmeshev, Dmitry
- Holmqvist, Staffan
- Kaufmann, Max
- Werneburg, Sebastian
- Vistnes, Stephanie
- Stockley, John H.
- Steindel, Maike
- Bhaduri, Aparna
- Mayer, Simone
- Engler, Jan Broder
- Bayraktar, Omer A.
- Franklin, Robin J. M.
- Haeussler, Maximilian
- Reynolds, Richard
- Schafer, Dorothy P.
- Friese, Manuel A.
- Shiow, Lawrence R.
- Kriegstein, Arnold R.
- Rowitch, David H.
- Venue
- Nature
- Published
- 2019-07-17
- Volume
- 573
- Issue
- 7772
- Pages
- 75-82
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6731122
- OpenAlex
- W2951560273
- Cited by
- 638
- References
- 56
- Citations by year
- 2026: 69 · 2025: 100 · 2024: 118 · 2023: 91 · 2022: 99 · 2021: 89 · 2020: 56 · 2019: 15
- FWCI
- 47.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship@UMassChan (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Wellcome Trust (108139, 108139/B/15/Z, 108139/Z/15/Z)
- Multiple Sclerosis Society
- Rosetrees Trust (M525-CD2)
- Cambridge University Hospitals (146281)
- Medical Research Council (MC_PC_12009, MR/K008803/1, MR/M010503/1)
- Biotechnology and Biological Sciences Research Council (1517905, BB/I013210/1)
- National Human Genome Research Institute (U41HG002371)
- National Institute of Neurological Disorders and Stroke (F32NS103266, R35NS097305, R01NS040511)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- multiple sclerosis, neuronal vulnerability, meningeal inflammation, reactive astrocytes, microglial activation, macrophages, MS plaques, long non-coding RNA, glial activation, single-nucleus RNA sequencing
- MeSH terms
- RNA-Seq, Adult, Animals, Astrocytes, Autopsy, Female, Humans, Macrophages, Male, Middle Aged, Multiple Sclerosis, Myelin Sheath, Neurons, Oligodendroglia, Phagocytosis, RNA, Small Nuclear, Cryopreservation, Microglia, Homeodomain Proteins, Cell Lineage, Mice, Transcriptome
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