Neuronal vulnerability and multilineage diversity in multiple sclerosis.

Adult Animals Astrocytes / metabolism Autopsy Cell Lineage Cryopreservation Female Homeodomain Proteins / metabolism Humans Macrophages / metabolism Male Mice Microglia / metabolism Middle Aged Multiple Sclerosis / genetics Myelin Sheath / metabolism Neurons / metabolism Oligodendroglia / metabolism Phagocytosis RNA, Small Nuclear / analysis RNA-Seq Transcriptome / genetics

Journal

Nature
ISSN: 1476-4687
Titre abrégé: Nature
Pays: England
ID NLM: 0410462

Informations de publication

Date de publication:
09 2019
Historique:
received: 26 10 2018
accepted: 12 06 2019
pubmed: 19 7 2019
medline: 31 3 2020
entrez: 19 7 2019
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41586-019-1404-z PMID: 31316211 PMC: PMC6731122
pubmed: 31316211
doi: 10.1038/s41586-019-1404-z
pii: 10.1038/s41586-019-1404-z
pmc: PMC6731122
mid: EMS83370
doi:

Substances chimiques

CUX2 protein, human 0
Homeodomain Proteins 0
RNA, Small Nuclear 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

75-82

Subventions

Organisme : NINDS NIH HHS
ID : R01 NS040511
Pays : United States
Organisme : Medical Research Council
ID : G0701476
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_12009
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0300336
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : U41 HG002371
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS097305
Pays : United States
Organisme : Medical Research Council
ID : MR/M010503/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0802545
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : F32 NS103266
Pays : United States
Organisme : Medical Research Council
ID : G0300338
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0700392
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 108139
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K008803/1
Pays : United Kingdom

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Auteurs

Lucas Schirmer (L)

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
Department of Paediatrics and Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
Department of Neurology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Division of Neonatology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.

Dmitry Velmeshev (D)

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.

Staffan Holmqvist (S)

Department of Paediatrics and Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.

Max Kaufmann (M)

Institute of Neuroimmunology and Multiple Sclerosis, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Sebastian Werneburg (S)

Department of Neurobiology and the Brudnik Neuropsychiatric Institute, University of Massachusetts Medical School, Worcester, MA, USA.

Diane Jung (D)

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.

Stephanie Vistnes (S)

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
Division of Neonatology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.

John H Stockley (JH)

Department of Paediatrics and Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.

Adam Young (A)

Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.

Maike Steindel (M)

Department of Paediatrics and Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.

Brian Tung (B)

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.

Nitasha Goyal (N)

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.

Aparna Bhaduri (A)

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.

Simone Mayer (S)

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.

Jan Broder Engler (JB)

Institute of Neuroimmunology and Multiple Sclerosis, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Omer A Bayraktar (OA)

Department of Paediatrics and Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.

Robin J M Franklin (RJM)

Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.

Maximilian Haeussler (M)

Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA, USA.

Richard Reynolds (R)

Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.

Dorothy P Schafer (DP)

Department of Neurobiology and the Brudnik Neuropsychiatric Institute, University of Massachusetts Medical School, Worcester, MA, USA.

Manuel A Friese (MA)

Institute of Neuroimmunology and Multiple Sclerosis, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Lawrence R Shiow (LR)

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
Division of Neonatology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.

Arnold R Kriegstein (AR)

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.
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA. arnold.kriegstein@ucsf.edu.

David H Rowitch (DH)

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.
Department of Paediatrics and Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. dhr25@medschl.cam.ac.uk.
Division of Neonatology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA. dhr25@medschl.cam.ac.uk.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Neuronal vulnerability and multilineage...
questionsmedicales.fr › Eucaryotes › Animaux › Neuronal vulnerability and multilineage...
questionsmedicales.fr › Cellules › Névroglie › Astrocytes › Neuronal vulnerability and multilineage...
questionsmedicales.fr › Sciences sociales › Criminologie › Sciences légales › Médecine légale › Autopsie › Neuronal vulnerability and multilineage...
questionsmedicales.fr › Phénomènes physiologiques des appareils urinaire et reproducteur › Phénomènes physiologiques de la reproduction › Reproduction › Développement embryonnaire et foetal › Développement embryonnaire › Lignage cellulaire › Neuronal vulnerability and multilineage...
questionsmedicales.fr › Techniques d'investigation › Conservation biologique › Cryoconservation › Neuronal vulnerability and multilineage...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de liaison à l'ADN › Protéines à homéodomaine › Neuronal vulnerability and multilineage...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Neuronal vulnerability and multilineage...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Phagocytes › Macrophages › Neuronal vulnerability and multilineage...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Neuronal vulnerability and multilineage...
questionsmedicales.fr › Cellules › Névroglie › Microglie › Neuronal vulnerability and multilineage...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Neuronal vulnerability and multilineage...
questionsmedicales.fr › Maladies du système immunitaire › Maladies auto-immunes › Maladies auto-immunes du système nerveux › Maladies démyélinisantes auto-immunes du SNC › Sclérose en plaques › Neuronal vulnerability and multilineage...
questionsmedicales.fr › Cellules › Neurones › Neurofibres › Gaine de myéline › Neuronal vulnerability and multilineage...
questionsmedicales.fr › Cellules › Neurones › Neuronal vulnerability and multilineage...
questionsmedicales.fr › Cellules › Névroglie › Oligodendroglie › Neuronal vulnerability and multilineage...
questionsmedicales.fr › Phénomènes du système immunitaire › Phagocytose › Neuronal vulnerability and multilineage...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN non traduit › Petit ARN non traduit › Petit ARN nucléaire › Neuronal vulnerability and multilineage...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ARN › RNA-Seq › Neuronal vulnerability and multilineage...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Transcriptome › Neuronal vulnerability and multilineage...