Neuronal vulnerability and multilineage diversity in multiple sclerosis

Lucas Schirmer, Dmitry Velmeshev, Staffan Holmqvist, Max Kaufmann, Sebastian Werneburg, Diane Jung, Stephanie Vistnes, John H. Stockley, Adam Young, Maike Steindel, Brian Tung, Nitasha Goyal, Aparna Bhaduri, Simone Mayer, Jan Broder Engler, Omer A. Bayraktar, Robin J. M. Franklin, Maximilian Haeussler, Richard Reynolds, Dorothy P. Schafer, Manuel A. Friese, Lawrence R. Shiow, Arnold R. Kriegstein () and David H. Rowitch ()
Additional contact information
Lucas Schirmer: University of California, San Francisco
Dmitry Velmeshev: University of California, San Francisco
Staffan Holmqvist: University of Cambridge
Max Kaufmann: University Medical Center Hamburg–Eppendorf
Sebastian Werneburg: University of Massachusetts Medical School
Diane Jung: University of California, San Francisco
Stephanie Vistnes: University of California, San Francisco
John H. Stockley: University of Cambridge
Adam Young: University of Cambridge
Maike Steindel: University of Cambridge
Brian Tung: University of California, San Francisco
Nitasha Goyal: University of California, San Francisco
Aparna Bhaduri: University of California, San Francisco
Simone Mayer: University of California, San Francisco
Jan Broder Engler: University Medical Center Hamburg–Eppendorf
Omer A. Bayraktar: University of Cambridge
Robin J. M. Franklin: University of Cambridge
Maximilian Haeussler: University of California, Santa Cruz
Richard Reynolds: Imperial College London
Dorothy P. Schafer: University of Massachusetts Medical School
Manuel A. Friese: University Medical Center Hamburg–Eppendorf
Lawrence R. Shiow: University of California, San Francisco
Arnold R. Kriegstein: University of California, San Francisco
David H. Rowitch: University of California, San Francisco

Nature, 2019, vol. 573, issue 7772, 75-82

Abstract: Abstract 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.

Date: 2019
References: Add references at CitEc
Citations: View citations in EconPapers (12)

Downloads: (external link)
https://www.nature.com/articles/s41586-019-1404-z Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:573:y:2019:i:7772:d:10.1038_s41586-019-1404-z

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-019-1404-z

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().