Functional genomic analyses highlight a shift in Gpr17‐regulated cellular processes in oligodendrocyte progenitor cells and underlying myelin dysregulation in the aged mouse cerebrum. Issue 4 (5th March 2021)

• Record Type: Journal Article
• Authors: Rivera, Andrea D.; Pieropan, Francesca; Chacon‐De‐La‐Rocha, Irene; Lecca, Davide; Abbracchio, Maria P.; Azim, Kasum; Butt, Arthur M.
• Is Part Of: Aging cell. Volume 20:Issue 4(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-03-05
• Subjects: ageing -- brain -- drug discovery -- GPR17 -- myelin -- oligodendrocyte -- oligodendrocyte precursor -- remyelination; Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.13335
• Languages: English
• ISSNs: 1474-9718

Abstract

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. Abstract : Ageing reduces the number of OPCs and their 'stemness'. Genomic analysis resolved key mechanisms underpinning the age related decline in OPCs, most notably reduced expression of Gpr17 in a subpopulation of differentiation committed OPCs. Pharmacogenomics identified small molecules that have the potential to rejuvenate OPCs and promote myelination and repair.