Parkinson’s Disease

Parkinson’s disease (PD), with a prevalence of 2% of the population over the age of 65, is one of the most common neurodegenerative disorders and is characterized by resting tremor, rigidity, and bradykinesia. Current treatments are only symptomatic and do not alter the progression of the disease. PD patients, even under the best circumstances, typically deteriorate over time and experience considerable motor and cognitive disability in the years after diagnosis.

 

The neuropathology of PD is characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and the appearance of Lewy bodies in the remaining neurons. Although the primary cause of PD is still unknown, there has been growing evidence that mitochondrial dysfunction and oxidative stress contribute to the pathogenesis of PD.  Oxidative damage and partial deficiencies in mitochondrial complex I in the nigrostriatal pathway have been 

 

 

 

 

8-oxoG has been demonstrated to be significantly higher in PD postmortem brain samples than in age-matched controls. The DNA oxidative damage noted in PD, though, is not solely observed in the nigrostriatal pathway as 8-oxoG has been observed to be elevated in lymphocytes, cerebrospinal fluid, and serum.  Urinary levels of 8-oxoG are also elevated in PD patients, correlating with the progression of the disease. Relatedly, the expression of enzymes, such as MTH1, OGG1, and MUTYH, that repair or remove oxidized guanine bases are seen to be upregulated in PD brains suggesting that these three enzymes cooperate in mtDNA repairing in PD brains.  Specifically, immunostaining for OGG1-2a, the form of OGG1 localized with mitochondria, revealed intense cytoplasmic staining in the dopaminergic neurons in the SN in PD patients, while immunoreactivity was rarely observed in any brain regions of control subjects.

These studies all point to the critical role of oxidative stress and mitochondrial dysfunction in the pathogenesis of PD. Similarly, the enzymes responsible for the minimization of the damage from oxidative stress represent promising targets for treatment of PD. Improving the functionality of OGG1 in PD patients may therefore positively impact the pathology of PD.

proposed to contribute to the selective loss of dopaminergic neurons in PD. Dopaminergic neurons in the SN exhibit high levels of pro-oxidant iron and low levels of the antioxidant glutathione, and are therefore particularly vulnerable to oxidative stress and oxidative stress-induced somatic mitochondrial DNA mutations.