Changes in the Oligodendrocyte Progenitor Cell Proteome with Ageing

Abstract

Following central nervous system (CNS) demyelination, adult oligodendrocyte progenitor cells (OPCs) can differentiate into new myelin-forming oligodendrocytes in a regenerative process called remyelination. While 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 to their adult counterparts. The amount of myelin-associated proteins, and proteins associated with oxidative phosphorylation, inflammatory responses and actin cytoskeletal organization increased with age, while 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.

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

“…This is illustrated further by expression of YFP+ cells in each OL stage as a proportion of total YFP+ cells, which indicates a differentiation block of aged OPCs into COPs expressing Gpr17+ that regulates the transition from OPCs to MOLs (Viganò et al, 2016). To examine this further, we used chromogenic immunostaining (Figure 3e), together with qPCR to confirm Gpr17 mRNA is significantly and markedly decreased in ageing (Figure 3f), and inducible expression of eGFP in Gpr17+ COPs (Figure 3g); this is supported by a concurrent report that Gpr17 protein and mRNA are reduced in ageing (de la Fuente et al, 2020). Chromogenic immunolabelling is exceptionally sensitive and demonstrates that in the ageing brain, few cells exhibit the dense immunostaining of cellular processes that is characteristic of younger brain (Figure 3d), and instead, COPs are either dimly immunostained (Figure 3e, black arrows) or in many cases, the cell somata alone are immunopositive (Figure 3e, white arrows).…”

“…Transcriptomic studies have become increasingly important in understanding ageing processes in human and rodent oligodendrocytes (Azim et al, 2017(Azim et al, , 2020de la Fuente et al, 2020;Jäkel et al, 2019;Marques et al, 2016;Soreq et al, 2017). Here, using a combined transcriptomic and neurobiology approach we have identified essential oligodendroglial genes amongst the most dysregulated in the ageing mouse cerebrum, most notably Gpr17, which specifically decorates a subpopulation of differentiation committed OPCs (COPs) that are in transition to mature myelinating oligodendrocytes (MOLs) and react rapidly to brain pathology (Lecca et al, 2020).…”

Oxidative stress and impaired oligodendrocyte precursor cell differentiation in neurological disorders

“…The reduced differentiation and (re)myelination capacity of aged OPCs appears to be further compromised in neurodegenerative disorders [32][33][34][35]. In schizophrenia, various signalling pathways are impaired, with cell division pathways upregulated (e.g.…”

Intersection between ageing-related Genes and SARS-CoV-2 Interactome: Is it higher than expected?

“…The modifications in the APEX expression have been correlated with increased senescence [64]. In [70] the synergistic downregulation of both APEX and NPM1 has been clearly observed in oligodendrocyte cells in relation to ageing.…”