Genome integrity and disease prevention in the nervous system

Abstract

Multiple DNA repair pathways maintain genome stability and ensure that DNA remains essentially unchanged over the life of a cell. Various human diseases occur if DNA repair is compromised, and most of these impact the nervous system, in some cases exclusively. However, it is often unclear what specific endogenous damage underpins disease pathology. Generally, the types of causative DNA damage are associated with replication, transcription, or oxidative metabolism; other direct sources of endogenous lesions may arise from aberrant topoisomerase activity or ribonucleotide incorporation into DNA. This review focuses on the etiology of DNA damage in the nervous system and the genome stability pathways that prevent human neurologic disease.

Keywords: DNA damage; genome stability; nervous system; neurodevelopment; neurologic disease.

Figure 1.

Endogenous DNA damage relevant to diseases of the nervous system. Multiple types of endogenous lesions can impact the nervous system at all stages of development and maturity. Replication stress primarily affects proliferating neural progenitors. rNTPs can become incorporated into the DNA via DNA polymerases during neurogenesis. While this substantially impacts neural progenitors, it is also likely to occur throughout the developing and mature nervous system during DNA repair processes. In the mature nervous system, transcription-associated damage and aberrant topoisomerase activity will be a constant source of potential DNA damage. Oxidative damage can also impact immature cells but will be an ongoing threat to the mature nervous system.

Figure 2.

The BER pathway is essential in the nervous system. The BER system is required to correct SSBs and oxidative damage and is a critical main DNA repair pathway in the nervous system. The BER components listed in red have been identified in human neurodegenerative disease. The scaffold protein XRCC1 is key for efficient BER, and the repair enzymes aprataxin (APTX) and tyrosyl DNA phosphodiesterase-1 (TDP1) modify the 5′ and 3′ DNA ends, respectively, after damage to allow for religation/repair of the DNA break. Polynucleotide kinase/phosphatase (PNKP) has a dual kinase/phosphatase activity and can process both ends of a DNA break. Mutations in PNKP can result in different neurologic disease characterized by either microcephaly or neurodegeneration.