Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Apr 10;25(8):4187.
doi: 10.3390/ijms25084187.

DNA Damage and Parkinson's Disease

Gerd P Pfeifer  1
Affiliations
Review

DNA Damage and Parkinson's Disease

Gerd P Pfeifer. Int J Mol Sci. .

Abstract

The etiology underlying most sporadic Parkinson's' disease (PD) cases is unknown. Environmental exposures have been suggested as putative causes of the disease. In cell models and in animal studies, certain chemicals can destroy dopaminergic neurons. However, the mechanisms of how these chemicals cause the death of neurons is not understood. Several of these agents are mitochondrial toxins that inhibit the mitochondrial complex I of the electron transport chain. Familial PD genes also encode proteins with important functions in mitochondria. Mitochondrial dysfunction of the respiratory chain, in combination with the presence of redox active dopamine molecules in these cells, will lead to the accumulation of reactive oxygen species (ROS) in dopaminergic neurons. Here, I propose a mechanism regarding how ROS may lead to cell killing with a specificity for neurons. One rarely considered hypothesis is that ROS produced by defective mitochondria will lead to the formation of oxidative DNA damage in nuclear DNA. Many genes that encode proteins with neuron-specific functions are extraordinary long, ranging in size from several hundred kilobases to well over a megabase. It is predictable that such long genes will contain large numbers of damaged DNA bases, for example in the form of 8-oxoguanine (8-oxoG), which is a major DNA damage type produced by ROS. These DNA lesions will slow down or stall the progression of RNA polymerase II, which is a term referred to as transcription stress. Furthermore, ROS-induced DNA damage may cause mutations, even in postmitotic cells such as neurons. I propose that the impaired transcription and mutagenesis of long, neuron-specific genes will lead to a loss of neuronal integrity, eventually leading to the death of these cells during a human lifetime.

Keywords: DNA damage; DNA repair; Parkinson’s disease; mitochondria; mutations; transcription.

PubMed Disclaimer

Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Production of reactive oxygen species (ROS) in dysfunctional mitochondria and by dopamine redox cycling. (A). ROS produced in dysfunctional mitochondria can diffuse into the nucleus to cause DNA damage. (B). Dopamine oxidation generates reactive oxygen species (ROS).
Figure 2
Figure 2
Major oxidative DNA damage products produced by ROS and DNA repair mechanisms. (A). Damaged DNA bases induced by ROS. (B). DNA repair mechanisms. Base excision repair (BER) is shown on the left. This pathway exists as two types of mechanisms, short-patch and long-patch BER that require different proteins. Nucleotide excision repair (NER) is shown on the right. This pathway is subdivided into global NER and transcription-coupled NER, which operates in transcribed genes. Key protein factors involved in the different repair mechanisms are shown.
Figure 3
Figure 3
Production of ROS and cytokines by inflammatory processes in the brain. Created with Biorender.com. Accessed 18 March 2024.
Figure 4
Figure 4
Hypothesis of how ROS generate detrimental oxidative DNA damage in long neuron-specific genes. DNA-damaging ROS are produced in dysfunctional mitochondria after exposure to mitochondrial toxins, during the aging process, or because of a genetic predisposition. ROS damages nuclear DNA, leading to the formation of transcription blocking lesions in long genes. The lesions may also cause permanent mutations leading to neuronal dysfunction and cell death.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Cherian A., Divya K.P., Vijayaraghavan A. Parkinson’s disease—Genetic cause. Curr. Opin. Neurol. 2023;36:292–301. doi: 10.1097/WCO.0000000000001167. - DOI - PubMed
    1. Nalls M.A., Blauwendraat C., Vallerga C.L., Heilbron K., Bandres-Ciga S., Chang D., Tan M., Kia D.A., Noyce A.J., Xue A., et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: A meta-analysis of genome-wide association studies. Lancet Neurol. 2019;18:1091–1102. doi: 10.1016/S1474-4422(19)30320-5. - DOI - PMC - PubMed
    1. Lopez-Otin C., Blasco M.A., Partridge L., Serrano M., Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023;186:243–278. doi: 10.1016/j.cell.2022.11.001. - DOI - PubMed
    1. Antony P.M., Diederich N.J., Kruger R., Balling R. The hallmarks of Parkinson’s disease. FEBS J. 2013;280:5981–5993. doi: 10.1111/febs.12335. - DOI - PubMed
    1. Wilson D.M., 3rd, Cookson M.R., Van Den Bosch L., Zetterberg H., Holtzman D.M., Dewachter I. Hallmarks of neurodegenerative diseases. Cell. 2023;186:693–714. doi: 10.1016/j.cell.2022.12.032. - DOI - PubMed

Substances