Transcriptional mutagenesis by 8-oxodG in α-synuclein aggregation and the pathogenesis of Parkinson’s disease

Parkinson’s disease (PD) is an age-related progressive neurodegenerative disease associated with selective loss of dopaminergic neurons. The characteristic hallmark of the disease is intracytoplasmic proteinacious inclusion bodies called Lewy bodies, primarily consisting of a presynaptic protein α-synuclein. Oxidative stress-mediated damage to macromolecules have been shown to occur frequently in PD. Oxidative damage to DNA in the form of oxidized guanine (8-oxodG) accumulates in both the mitochondrial and nuclear DNA of dopaminergic neurons of the substantia nigra in PD. 8-oxodG-mediated transcriptional mutagenesis has been shown to have the potential to alter phenotype of cells through production of mutant pool of proteins. This review comprehensively summarizes the role of oxidative stress-mediated damage incurred during neurodegeneration, and highlights the scope of transcriptional mutagenesis event in leading to α-synuclein aggregation as seen in PD. Mutations caused by oxidative stress can lead to protein aggregation in the brains of people with Parkinson's disease. In a review article, a team led by Yoon-Seong Kim from the University of Central Florida in Orlando, US, discusses the possibility of how an excess of free radicals produced by oxygen metabolism can modify guanine, one of the four letters of DNA. In people with Parkinson's disease, the altered form of guanine is known to accumulate in the DNA of neurons found in the region of the brain most affected by the disease. There, the oxidized guanine can lead to genetically altered mRNA via transcriptional mutagenesis and subsequent mutated proteins. If this happens to the gene encoding α-synuclein, it may affect the normal protein and form aggregates inside neurons, leading to the hallmark neurodegeneration seen in Parkinson's disease.