Open AccessFunctional genomic analyses highlight a shift in Gpr17 ‐regulated cellular processes in oligodendrocyte progenitor cells and underlying myelin dysregulation in the aged mouse cerebrum
Author(s) -
Rivera Andrea D.,
Pieropan Francesca,
ChaconDeLaRocha Irene,
Lecca Davide,
Abbracchio Maria P.,
Azim Kasum,
Butt Arthur M.
Publication year - 2021
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13335
Subject(s) - biology , oligodendrocyte , myelin , remyelination , neuroscience , progenitor cell , multiple sclerosis , ageing , progenitor , central nervous system , microbiology and biotechnology , stem cell , genetics , immunology
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.