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bioRxiv · 10.1101/2020.10.26.354746

Functional genomic analyses highlights a shift in Gpr17-regulated cellular processes in oligodendrocyte progenitor cells (OPC) and underlying myelin dysregulation in the aged forebrain

Rivera, A. D.·Pieropan, F.·Chacon De La Rocha, I.·Lecca, D.·Abbracchio, M. P.·Azim, K.·Butt, A. M.
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Abstract

Brain aging 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 aging 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 aging hinders the development of regenerative strategies. Here, our combined systems biology and neurobiological approach demonstrates that oligodendroglial and myelin genes are amongst the most altered in the aging mouse cortex. This was underscored by the identification of causal links between signaling pathways and their downstream transcriptional networks that define oligodendroglial disruption in aging. The results highlighted that the G-protein coupled receptor GPR17 is central to the disruption of OPC in aging and this was confirmed by genetic fate mapping and cellular analyses. Finally, we used systems biology strategies to identify therapeutic agents that rejuvenate OPC and restore myelination in age-related neuropathological contexts.

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Rivera, A. D., Pieropan, F., Chacon De La Rocha, I., Lecca, D., Abbracchio, M. P., Azim, K., Butt, A. M.. 2020-10-26. Functional genomic analyses highlights a shift in Gpr17-regulated cellular processes in oligodendrocyte progenitor cells (OPC) and underlying myelin dysregulation in the aged forebrain. https://doi.org/10.1101/2020.10.26.354746

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