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

Dedicated to the memory of Dr. George Bartzokis. We who have come late to this field may not have known him, but we recognize the strength of the conceptual foundation that he laid, and upon which many of the ideas of this review are built. We mourn his untimely passing in August 2014
https://doi.org/10.1016/j.mad.2016.05.006Get rights and content

Highlights

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.

Introduction

Research into neurological disorders, particularly the age-associated dementias, focuses heavily on the nerve cell. For example, the most common age-associated dementia is Alzheimer’s disease (AD), whose hallmark pathologies of amyloid plaque formation and neurofibrillary tangles have typically been studied primarily for their impact on the neurons of the brain. Indeed, the very name, neurodegenerative disease, draws attention towards the striking loss of neuronal cell bodies and processes, and away from the roles of a variety of other brain cells in disease pathogenesis. With the failure of clinical trials based on this neurocentric outlook and the importance of developing alternative disease models, this perspective is beginning to broaden. Neuroinflammation and the role of the microglial cell are increasingly recognized as important players in AD (Heneka et al., 2015). Vascular problems and the participation of the endothelial cells is also gaining attention (Iadecola, 2013, Marchesi, 2011) as is the role of astrocytes (Rodriguez et al., 2009). In this review, we focus on the role of yet another cell type that is a likely contributor to the appearance of dementia, the oligodendrocyte (OL).

White matter (WM) degeneration and abnormalities in the aging brain have been well established over the years, if not fully appreciated. Evidence for the involvement of myelin abnormalities in the process of aging is compelling. Indeed the initial WM decline in the aging brain begins at about ∼45 years of age (Bartzokis et al., 2001, Bartzokis et al., 2003, Sperling et al., 2014). This puts WM changes as a strong correlate of aging, and certainly as strong as the modest decline found in neuron numbers during normal healthy aging (Mortera and Herculano-Houzel, 2012). The changes may also be one of the earliest events in AD pathogenesis. The significance of the oligodendrocyte to aging and neurodegenerative disease is further emphasized by its unusual sensitivity to DNA damage, in particular oxidative lesions. Exploring such intriguing temporal correlations and the clinical relationship between WM abnormalities and cognitive decline (Provenzano et al., 2013), may reveal important and early facets of the underlying neurobiology of prodromal late life dementias such as Alzheimer’s.

Section snippets

The life cycle of OLs and myelin formation

During human development, the development of the OL lineage begins at about nine weeks of gestation, when OL progenitor cells (OPC) first appear (Jakovcevski et al., 2009). These OPC, also known as NG2 cells, proliferate and become the dominant myelin-related cell type in the telencephalon until 18 weeks of gestation (Jakovcevski et al., 2009). Then, until about 27 weeks of gestation, the OPC differentiate into late OL progenitors or PreOLs by extending their cellular processes to enwrap

Myelination is uniquely expanded in human cortex

Myelination is a relatively recent evolutionary development that greatly enhances neural transmission in vertebrates. The conduction velocity of myelinated fibers is estimated to be at least 10-fold faster than that of unmyelinated fibers of the same diameter (Salami et al., 2003). Further, despite the classical dichotomy of white matter versus gray matter (GM), myelination is found in both (Krimer et al., 1997). Nonetheless in the human brain (the prefrontal lobe in particular) it is the

Loss of myelination is a pathological hallmark of the aging and AD brain

The seminal observations in this area are the pioneering MRI studies by Bartzokis et al. showing that the developmental curve of WM volume in healthy human brain resembles an inverted-U shape (Bartzokis et al., 2001). The WM volume in the frontal and temporal lobe increases at the beginning of adolescence and peaks at 45 years of age, before beginning a slow decline. Such a pattern of WM change is the inverse of that of the gray matter, which begins to reduce in the second decade of life (

DNA damage in oligodendrocytes is commonly found in WM lesions

The cellular pathology underlying WMH is best illustrated by the pathology of the well-known demyelinating disease, multiple sclerosis (MS). MS is characterized by foci of demyelinating plaques which are commonly imaged as WMH in MRI studies (West et al., 2014). Postmorterm analysis of MS brain found that these WMH are plaques with loss of myelin, heavy astrogliosis and strong microglia activation (Moll et al., 2011, Schmierer et al., 2007). In these WMH, demyelinating lesions, oxidative DNA

Defects in single strand break repair

Bulky lesions are dangerous modifications to the DNA; they disrupt transcription and often lead to single strand breaks (SSBs). These SSBs are usually repaired by processes known as base excision repair (BER), nucleotide excision repair (NER) or mismatch repair (MMR). BER is responsible for most oxidative or alkylation DNA damage. NER is most commonly used to repair SSB occur after UV irradiations. In mitotic cells, genomic errors formed during DNA replication are repaired by MMR. Mutations in

Oxidative stress is the ultimate cause of DNA damage to OL

DNA damage of OLs in WM can be caused by the chronic oxidative stress of the AD brain (Al-Mashhadi et al., 2015). This linkage between oxidation and DNA damage is best illustrated, by the pathology of multiple sclerosis (MS). MS is a progressive and irreversible demyelination triggered by an excessive autoimmune reaction to largely unknown antigens. Apoptosis with DNA fragmentation of cells in the OL lineage is frequent in MS plaques (Ozawa et al., 1994) where high levels of reactive oxidative

Aging OLs and their lineage-specific dependence on components of the DNA repair pathway

The aforementioned intrinsic properties of OL differentiation are predictably tied to the developmental program of myelination. Here we speculate that the special requirement for intact DNA repair pathways during OL development confers such additional cell type-specific risks to the OL lineage in the aging brain. These specific risks have resonance with dynamic aspects of OL development because of the possibility of activity-dependent, and DNA repair-dependent transcription of myelin-related

Conclusions

In a sentiment often attributed to Don Cleveland, neurodegenerative diseases are, in reality, diseases “of the neighborhood” (Ilieva et al., 2009). The meaning behind this statement is that failure of nervous system function is as much a failure of the web of cell-cell interactions as it is the demise of any one specific cell type. The value of this perspective is that if we assume that it is the web that fails, then it is easier to imagine that the first step in the decline can be taken by any

Acknowledgments

The present work is funded by GRF16101315 and GRF660813 from the Research Grant Council, Hong Kong SAR. Support was also received from the National Key Basic Research Program of China (2013CB530900) and the National Institutes of Health of the United States (NS71022)

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