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  • Published:

Genomic integrity and the ageing brain

Nature Reviews Neuroscience volume 16, pages 672–684 (2015)Cite this article

Subjects

Key Points

  • Although ageing is a difficult concept to define biologically, the accumulation of unrepaired DNA damage and the accompanying loss of genomic integrity are now regarded as signatures of ageing.

  • DNA damage in neurons probably begins accumulating even during the developmental process, and is also a by-product of normal physiological functions such as gene transcription and enhanced neuronal activity.

  • Neurons are permanently postmitotic and therefore cannot perform double-stranded break repair through the more accurate homologous recombination pathway. Consequently, neurons adopt a selective repair approach in which genes that are actively transcribed are repaired more than elements in the rest of the genome.

  • Neither the transcriptional programme nor the activity pattern of any two neurons is likely to be identical. Therefore, the regions of aggressive DNA repair, as well as those that are poorly maintained, probably vary from cell to cell.

  • The clear implication of this genetic heterogeneity is that with age, the genome of each and every neuron in the brain evolves a unique configuration of 'stress marks'. These differences may lead to regionally variable genetic patterns that are somatic in origin and may underlie the different molecular phenotypes observed in different neurodegenerative diseases.

  • Many researchers have commented on the relationship between mutations in components of the DNA repair machinery and the occurrence of major developmental abnormalities and syndromes that include premature ageing. However, little is known about the DNA repair capacity of the cells of the ageing brain.

  • As DNA repair is a lifelong process and because an early developmental arrest would mask the consequences of a somatically acquired loss of DNA repair fidelity, virtually nothing is known about how non-genomic factors, such as a gradual change in cellular signalling, epigenetic landscape, or even the expression pattern of non-protein coding miRNAs, may better explain the cause of various ageing-related neurodegenerative disorders.

Abstract

DNA damage is correlated with and may drive the ageing process. Neurons in the brain are postmitotic and are excluded from many forms of DNA repair; therefore, neurons are vulnerable to various neurodegenerative diseases. The challenges facing the field are to understand how and when neuronal DNA damage accumulates, how this loss of genomic integrity might serve as a 'time keeper' of nerve cell ageing and why this process manifests itself as different diseases in different individuals.

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Figure 1: DNA breakage is a part of normal development.
Figure 2: Causes of DNA damage in the developing, mature and ageing nervous system.
Figure 3: Neurodegeneration in ageing neurons resulting from a reduction of DNA integrity.
Figure 4: DNA damage and the onset of specific neurodegenerative diseases.

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Acknowledgements

This work was supported by grants from The Hong Kong University of Science and Technology, the National Key Basic Research Program of China (2013CB530900), the Research Grants Council, the Hong Kong Special Administrative Region (HKUST12/CRF/13G and GRF660813), the US National Institutes of Health (NS70193), and the BrightFocus Foundation (A2012101).

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Authors and Affiliations

  1. Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong

    Hei-man Chow & Karl Herrup

  2. Institute for Advanced Study, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong

    Hei-man Chow

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Correspondence to Karl Herrup.

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Glossary

Senescence

A state of cell cycle arrest that can arise in proliferating cells after a finite number of cell divisions. Senescence can also occur prematurely in dividing cells as a result of stress or a detrimental environment.

Synapsis

The pairing of replicated homologous chromosomes during prophase I of meiosis.

Crossing over

The reciprocal exchange of genetic material between non-sister chromatids during synapsis of meiosis I.

V(D)J recombination

Also known as somatic recombination, this process occurs in B and T lymphocytes that are generated during early development via somatic assembly of component gene segments. V(D)J recombination enables diversity in the antigen recognition machinery.

Aneuploidy

The presence of an abnormal number of chromosomes in a cell.

Microaneuploidies

Genomic alterations that result in unbalanced copy numbers of subchromosomal regions.

Copy number variation

Refers to when the number of copies of a particular gene varies from one individual to the next.

Chromosomal mosaicism

Refers to when an individual has two or more cell populations with a different chromosomal makeup.

DNA supercoiling

Refers to the over- or under-winding of a DNA strand.

Hypomorphs

Mutations in genes that have a similar but weaker effect than the corresponding wild-type gene.

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Chow, Hm., Herrup, K. Genomic integrity and the ageing brain. Nat Rev Neurosci 16, 672–684 (2015). https://doi.org/10.1038/nrn4020

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