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Changes in the Oligodendrocyte Progenitor Cell Proteome with Ageing

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Following central nervous system (CNS) demyelination, adult oligodendrocyte progenitor cells (OPCs) can differentiate into new myelin-forming oligodendrocytes in a regenerative process called remyelination. Although remyelination is very efficient in young adults, its efficiency declines progressively with ageing. Here we performed proteomic analysis of OPCs freshly isolated from the brains of neonate, young and aged female rats. Approximately 50% of the proteins are expressed at different levels in OPCs from neonates compared with their adult counterparts. The amount of myelin-associated proteins, and proteins associated with oxidative phosphorylation, inflammatory responses and actin cytoskeletal organization increased with age, whereas cholesterol-biosynthesis, transcription factors and cell cycle proteins decreased. Our experiments provide the first ageing OPC proteome, revealing the distinct features of OPCs at different ages. These studies provide new insights into why remyelination efficiency declines with ageing and potential roles for aged OPCs in other neurodegenerative diseases.

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Highlights

  • Quantitative proteome of neonatal, young, and aged OPCs.

  • 50% of the proteome is differentially expressed between neonatal and adult OPCs.

  • Myelin proteins are increased, and cholesterol synthesis proteins decreased with age.

  • Proteins associated with other neurodegenerative diseases are increased in aged OPCs.

Aging
stem cells
neurodegenerative diseases
neurobiology
progenitor cells
multiple sclerosis
myelin
oligodendrocyte
regeneration

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This article contains supplemental data.

Funding and additional information—This work was supported by grants from the UK Multiple Sclerosis Society (MS50), MedImmune, The Adelson Medical Research Foundation and a core support grant from the Wellcome Trust and MRC to the Wellcome-Medical Research Council Cambridge Stem Cell Institute (203151/Z/16/Z). A.G.d.l.F. was also supported by an ECTRIMS postdoctoral fellowship from July 2018. R.M.L.Q. was supported by the Brazilian Science without Borders program (grant number 2030981/2014-14-AstraZeneca/Brazil/CNPq).

Author contributions—A.G.d.l.F., R.M.Q., C.A.J., and R.J.M.F. designed research; A.G.d.l.F., R.M.Q., and J.F.C. performed research; A.G.d.l.F., R.M.Q., and R.J.M.F. contributed new reagents/analytic tools; A.G.d.l.F., R.M.Q., T.G., and C.E.M. analyzed data; A.G.d.l.F., D.E.B., D.C.F., K.S.L., and R.J.M.F. wrote the paper; A.G.d.l.F. designed the figures, Planned the experiments, Conducted experiments, collected data, Interpreted the data; R.M.Q. planned experiments, conducted experiments, collected data, interpreted data; C.E.M. edited the manuscript and figures; D.E.B. and D.C.F. interpreted data; C.A.J. edited the manuscript Planned experiments Supervised the project; K.S.L. interpreted the data Supervised the project; C.P.G. edited the manuscript Planned the experiments Supervised the project; R.J.M.F. designed the figures, Interpreted the data, Supervised the project.

Conflict of interest—Authors declare no competing interests.

Abbreviations—The abbreviations used are:

    AD

    Alzheimer's disease

    b-FGF

    basic fibroblast growth factor

    BSA

    bovine seroalbumin

    ACN

    acetonitrile

    CNS

    central nervous system

    DMEM

    Dulbecco's modified essential medium

    DTT

    di-thiotreitol

    EAE

    experimental autoimmune encephalomyelitis

    FDR

    false discovery rate

    GO

    Gene Ontology

    HBSS

    Hank's balanced salt solution

    HD

    Huntington's disease

    HRP

    horse radish peroxidase

    IgM

    immunoglobulin M

    KEGG

    Kyoto Encyclopedia of Genes and Genomes

    LC-MS/MS

    liquid chromatography-tandem mass spectrometry

    LIMMA

    linear model for microarray analysis

    MS

    multiple sclerosis

    MS/MS

    tandem mass spectrometry

    MSA

    multiple system atrophy

    MWB

    Miltenyi wash buffer

    NDS

    normal donkey serum

    Neo

    neonatal

    OPC

    oligodendrocyte progenitor cell

    PBS

    phosphate buffered saline

    PC

    principal component

    PCA

    principal component analysis

    PD

    Parkinson's disease

    PDGF-aa

    platelet derived growth factor AA

    PFA

    paraformaldehyde

    PSM

    peptide-to-spectrum matches

    PVDF

    polyvinylidene fluoride

    RNA-seq

    RNA sequencing

    RT

    room temperature

    TBS

    tris-buffered saline

    TBST

    tris-buffered saline with 0.1% Tween

    TEAB

    triethylammonium bicarbonate

    TFA

    trifluoroacetic acid

    TMT

    tandem mass tag

    V

    volts.

Present address for Alerie G. de la Fuente: Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, United Kingdom.

Present address for Clare A. Jones: Talisman Therapeutics Ltd. Cambridge, United Kingdom.