Format

Send to

Choose Destination
Nature. 2019 Jul 17. doi: 10.1038/s41586-019-1404-z. [Epub ahead of print]

Neuronal vulnerability and multilineage diversity in multiple sclerosis.

Author information

1
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
2
Department of Paediatrics and Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
3
Department of Neurology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
4
Division of Neonatology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
5
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
6
Institute of Neuroimmunology and Multiple Sclerosis, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
7
Department of Neurobiology and the Brudnik Neuropsychiatric Institute, University of Massachusetts Medical School, Worcester, MA, USA.
8
Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
9
Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
10
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
11
Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA, USA.
12
Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
13
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA. arnold.kriegstein@ucsf.edu.
14
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA. arnold.kriegstein@ucsf.edu.
15
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA. dhr25@medschl.cam.ac.uk.
16
Department of Paediatrics and Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. dhr25@medschl.cam.ac.uk.
17
Division of Neonatology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA. dhr25@medschl.cam.ac.uk.

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.

PMID:
31316211
DOI:
10.1038/s41586-019-1404-z

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center