Genomic Stress Due to Incomplete DNA Base Excision Repair Results to Neuronal Death in Parkinson's Disease Model

An international collaboration of scientists from the Institute of Molecular Biology & Biotechnology of FORTH, the National and Kapodistrian University of Athens, and the University of Oslo discovered that incomplete DNA base excision repair (BER) promotes genomic stress that contributes to age-related neurodevelopmental disorders, like Parkinson's disease.

According to Medical XPress, the study reveal a new role for the BER pathway that underlies the pathogenesis of Parkinson's disease, aside from aging and mitochondrial dysfunction.

Base Excision Repair (BER) Pathway

According to a paper in Nature, the base excision repair (BER) pathway repairs most endogenous base lesions and atypical bases in the genome. Also, it corrects similar lesions produced by several groups of environmental agents.

Additionally, the BER pathway repairs the single-strand breaks in the DNA that resulted from the free radical reaction of deoxyribose residues that invariably contains blocked termini. Studies show that that the concept of BER is a complex process rather than a simple one that was previously known.

Creative Diagnostics added that BER might occur in the nucleus or mitochondria using different proteins to correct small base lesions. Defects in the BER pathway could result in cancer, shorten chronological lifespan in yeast. Scientists believe that BER has a number of promising targets that could improve cancer therapy.

But now, new research has found that an incomplete BER pathway may also lead to age-related neurodegenerative disorders, such as Parkinson's disease.

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Incomplete BER Pathway Source of Genomic Stress During Aging

In the study titled "Base Excision Repair Causes Age-Dependent Accumulation of Single-Stranded DNA Breaks That Contribute to Parkinson Disease Pathology" published in Cell Reports, researchers showed that base excision repair generates genomic stress that causes age-related neurodegenerative disorders in Caenorhabditis elegans as their Parkinson's disease model.

According to Medical Xpress, Parkinson's disease is the second most common neurodegenerative disorder associated with oxidative stress, genomic instability, mitochondrial dysfunction, and proteostasis imbalance. The study showed that dopaminergic neurons' high metabolic activity and low antioxidant capacity lead to damage in macromolecules, such as DNA.

BER pathway repairs the oxidative damage in the DNA from the effects of cytotoxic and mutagenic nucleobases. However, researchers found that incomplete processing of endogenous DNA base damage via the BER pathway leads to incomplete BER activity, resulting in neuronal cell death in C. elegans.

Furthermore, data from analysis using the whole-exome sequencing revealed an improved genetic variation in patients with Parkinson's disease via the BER pathway. This could indicate that the BER pathway might be a pathophysiology modulator or regulate susceptibility to Parkinson's disease in humans.

Researchers pointed out that the study's findings could be used in the development of a new therapeutic intervention to protect the brain during aging and prevent neuronal loss in patients with Parkinson's disease or any other age-related neurodegenerative disorders.