DNA damage in the oligodendrocyte lineage and its role in brain aging. (January 2017)

• Record Type: Journal Article
• Authors: Tse, Kai-Hei; Herrup, Karl
• Is Part Of: Mechanisms of ageing and development. Volume 161:Part A(2017)
• Page Start: 37
• Page End: 50
• Publication Date: 2017-01
• Subjects: Oligodendrocyte -- DNA damage -- Alzheimer's disease -- Progeriod syndromes -- White matter -- Aging brain; Aging -- Periodicals; Developmental biology -- Periodicals; Aging -- Periodicals; Developmental Biology -- Periodicals; Vieillissement -- Périodiques; Biologie du développement -- Périodiques; Aging; Developmental biology; Periodicals; 612.67
• DOI: 10.1016/j.mad.2016.05.006
• Languages: English
• ISSNs: 0047-6374

Abstract

Highlights: Myelin loss is a robust pathology for the aging brain and progeriod syndromes. White matter lesions are commonly tied with DNA damage in oligodendrocytes (OLs). OLs are highly vulnerable to oxidative stress and DNA damage in the aging brain. DNA repair proteins are essential for genomic integrity and myelin formation in OLs. 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.