Functional genomic analyses highlight a shift in Gpr17-regulated cellular processes in oligodendrocyte progenitor cells and underlying myelin dysregulation in the aged mouse cerebrum

Andrea D. Rivera, Francesca Pieropan, Irene Chacon-De-La-Rocha, Davide Lecca, Maria P. Abbracchio, Kasum Azim, Arthur M. Butt*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

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    Abstract

    Brain ageing is characterised by a decline in neuronal function and associated cognitive deficits. There is increasing evidence that myelin disruption is an important factor that contributes to the age-related loss of brain plasticity and repair responses. In the brain, myelin is produced by oligodendrocytes, which are generated throughout life by oligodendrocyte progenitor cells (OPCs). Currently, a leading hypothesis points to ageing as a major reason for the ultimate breakdown of remyelination in Multiple Sclerosis (MS). However, an incomplete understanding of the cellular and molecular processes underlying brain ageing hinders the development of regenerative strategies. Here, our combined systems biology and neurobiological approach demonstrate that oligodendroglial and myelin genes are amongst the most altered in the ageing mouse cerebrum. This was underscored by the identification of causal links between signalling pathways and their downstream transcriptional networks that define oligodendroglial disruption in ageing. The results highlighted that the G-protein coupled receptor Gpr17 is central to the disruption of OPCs in ageing and this was confirmed by genetic fate-mapping and cellular analyses. Finally, we used systems biology strategies to identify therapeutic agents that rejuvenate OPCs and restore myelination in age-related neuropathological contexts.

    Original languageEnglish
    Article numbere13335
    Number of pages14
    JournalAging Cell
    Volume20
    Issue number4
    Early online date5 Mar 2021
    DOIs
    Publication statusPublished - 1 Apr 2021

    Keywords

    • ageing
    • brain
    • drug discovery
    • GPR17
    • myelin
    • oligodendrocyte
    • oligodendrocyte precursor
    • remyelination
    • UKRI
    • BBRSC
    • BB/M029379/1
    • MRC
    • MR/P025811/1

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