DNA damage in the oligodendrocyte lineage and its role in brain aging

Abstract

Myelination is a recent evolutionary addition that significantly enhances the speed of transmission in the neural network. Even slight defects in myelin integrity impair performance and enhance the risk of neurological disorders. Indeed, myelin degeneration is an early and well-recognized neuropathology that is age associated, but appears before cognitive decline. Myelin is only formed by fully differentiated oligodendrocytes, but the entire oligodendrocyte lineage are clear targets of the altered chemistry of the aging brain. As in neurons, unrepaired DNA damage accumulates in the postmitotic oligodendrocyte genome during normal aging, and indeed may be one of the upstream causes of cellular aging - a fact well illustrated by myelin co-morbidity in premature aging syndromes arising from deficits in DNA repair enzymes. The clinical and experimental evidence from Alzheimer's disease, progeroid syndromes, ataxia-telangiectasia and other conditions strongly suggest that oligodendrocytes may in fact be uniquely vulnerable to oxidative DNA damage. If this damage remains unrepaired, as is increasingly true in the aging brain, myelin gene transcription and oligodendrocyte differentiation is impaired. Delineating the relationships between early myelin loss and DNA damage in brain aging will offer an additional dimension outside the neurocentric view of neurodegenerative disease.

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…White matter integrity is compromised during normal human brain aging, and this is exacerbated in subjects with cognitive impairment (Bennett and Madden, 2014; Liu et al, 2017). The mechanism underlying such demyelination involves oxidative DNA damage to oligodendrocytes (Tse and Herrup, 2017). …”

A human brain microphysiological system derived from induced pluripotent stem cells to study neurological diseases and toxicity

“…Myelin pathology is a rather frequent condition in demyelinating and inflammatory disorders such as multiple sclerosis and post-infectious diseases as well as other neurological diseases, such as acute and post-traumatic brain injury, stroke and neurodegenerative disorders (Fumagalli et al, 2016; Tse and Herrup, 2016). Moreover, the myelination process can be perturbed by exposure to chemicals and drugs (Garcia et al, 2005; Brubaker et al, 2009; Creeley et al, 2013) during brain development and in adulthood.…”

Oligodendrocytes in intracerebral hemorrhage

“…Thus, these molecules are used as markers for oligodendrocyte‐lineage cells. Classical OPC markers include NG2 (neuron‐glial antigen 2), PDGFRα, and Id2/4 . It should be noted that these markers are not OPC‐specific.…”

“…Classical OPC markers include NG2 (neuron-glial antigen 2), PDGFRα, and Id2/4. 34,[40][41][42][43][44][45] It should be noted that these markers are not OPC-specific. For example, NG2 is also expressed in mural cells and PDGFRα is also found in fibroblasts.…”

“…A recent study reported that TFEB (transcription factor EB) is highly enriched in pre-OLs and can be used as a pre-OL marker. 48 In addition, O4 has been also suggested as a pre-OL marker, 40,44,49 although there is also evidence showing that it is also expressed in mature-OLs. 50,51 Mature-OLs form myelin sheaths and express a group of unique proteins, including MYRF (myelin regulatory factor), 52 MBP (myelin basic protein), 38,44,53 MOG (myelin oligodendrocyte glycoprotein), [54][55][56] PLP (proteolipid protein), 44,53,57 and MAG (myelin-associated glycoprotein).…”