Parkinson's disease is a chronically progressive, age-related, fatal neurological disease. It is the second most common neurological disease, affecting about one percent of the population above 55 years of age (Martin et al., 2006). Clinical characteristics of PD consist of movement disorders, including bradykinesia, rigidity, resting tremor, postural instability, and gait disturbance (Stoker et. al., 2018). The neuropathological hallmarks of PD consist of the abnormal aggregation of toxic proteins known as Lewy Bodies and the depletion of dopaminergic neurons in the substantia nigra pars compacta (Martin et al., 2006). While current management options such as dopamine agonists and deep brain stimulation may improve or delay the manifestation of symptoms, there is currently no cure for PD. The most common treatment to slow the progression of symptoms includes the administration of levodopa, a precursor of dopamine. While this medication has been shown to significantly improve motor characteristics of PD in early stages, prolonged release of dopamine in the striatum has been associated with adverse effects including dyskinesia. Therefore, there is a significant need to develop a novel treatment that increases striatal levels of dopamine in a targeted and physiological manner as to prevent ongoing neurodegeneration and progression of pathology (Stoker et. al., 2018).

The objective of this review is to discuss urate as a potential biomarker and therapeutic target for Parkinson's Disease. Considering that oxidative stress is a core contributor to the development and progression of numerous neurodegenerative diseases, it is hypothesized that urate is a strong clinical candidate for a therapeutic target for PD (Crotty et. al., 2017). Urate is an antioxidant that is naturally present in the body and has emerged as a potential neuroprotectant to combat oxidative damage in PD (Paganoni & Schwarzschild, 2017). Dopaminergic neurons in the substantia nigra (SN) are particularly vulnerable to free radical attack due to their enzymatic and non-enzymatic metabolism as well as autoxidation of dopamine (Crotty et. al., 2017). In vitro models of neurodegeneration have demonstrated urate's ability to reduce oxidative stress, mitochondrial dysfunction and cellular death. As a powerful scavenger of peroxyl radicals and hydroxyl radicals, urate is also capable of inhibiting free radical-initiated DNA damage. Urate's neuroprotective effects may be attributed to its antioxidant properties which indicates that it may be involved in a shared mechanism of the pathophysiology of neurodegenerative diseases (Cipriani et al., 2011).

Early research on Parkinson's disease sparked interest in urate as a potential therapeutic target. Findings from a 1994 study by Church & Ward revealed decreased levels of urate in the substantia nigra and caudate of postmortem tissue from PD patients compared with controls. Furthermore, they found that dopamine oxidation rate constants were elevated in PD, suggesting that the disease is characterized by a state of 'pro-oxidative stress' (Church & Ward, 1994). Since these findings, numerous epidemiological, laboratory, and clinical trial studies have provided evidence for the roles of urate in neuroprotection. Two studies of particular relevance include the PRECEPT and the DATOP clinical trials as both found urate to be a strong predictor of Parkinson's disease development. The former study demonstrated that individuals in the highest quintile of serum urate concentration were 50% less likely than patients in the lowest quintile to develop a PD disability that would require dopaminergic therapy. In the latter study, it was further revealed that the risk of PD progression declined by 18% for every 1.5 mg/dl increase in serum urate concentration levels. These studies suggest a causal link between urate levels and PD progression, a notion which was further reinforced by the discovery that genetic determinants of urate concentration are also predictors of the development of PD. Ultimately, the combined findings from these studies deem urate an eligiblebiomarker of PD at different stages of disease progression (Paganoni & Schwarzschild, 2017).

Urate's capacity to modulate neuroinflammation and oxidative stress may be achieved via activation of the NF-E2-related factor 2 (Nrf2) antioxidant pathway (Crotty et. al., 2017). Nrf2 is a transcription factor that plays a significant role in impeding oxidative stress by modulating the transcription of oxidation-related genes (Zhang et. al., 2014). Findings from an in vivo study conducted by Huang et. al. demonstrated that uric acid increased mRNA and protein expressions of Nrf2 and its responsive genes in MPTP-induced PD mouse models. These transcriptional changes corresponded with enhanced behavioral and cognitive performances of PD mice as well as increased levels of TH-positive dopaminergic neurons in the SN (Huang et. al., 2017). Another study that induced a state of Parkinsonism using rotenone found that urate prevented the death of dopaminergic cells and at physiologically relevant concentrations, enhanced their functioning and survival in primary cultures of rat ventral mesencephalon. (Paganoni & Schwarzschild, 2017).

While the aforementioned findings present urate as a promising novel therapeutic target for Parkinson's Disease, there are caveats to these studies. One of the most significant limitations of PD research is that current animal models often fail to recreate the true pathophysiology of the disease (Potashkin et. al., 2011). Rodent and nonhuman primates are able to mimic symptoms of idiopathic PD when a Parkinsonian state is induced; however, results from animal model studies often fail to translate to clinical trials due to differences in physiology, anatomy, behavior, and regulation of gene expression between humans and the animal (Zhang et. al., 2014). For example, the animal studies previously mentioned induced states of PD using MPTP and rotenone. Both of these methods have been found to be controversial due to variability in cellular sensitivity and loss. Large variations in nigral cell loss and striatal dopamine loss were observed with MPTP, resulting in behavioral and motor deficits that did not fully represent those of idiopathic PD (Meredith & Rademacher, 2011). Similarly, the use of rotenone in animal models of PD has been shown to have great variation in its effects among individuals and species. For example, one study that treated mice with chronic rotenone found that they did not undergo the nigral degeneration that occurs in rotenone rat models. The significant variability that accompanies these methods is a major shortcoming for the use of animal models to evaluate treatment options for PD (Soderstrom et. al., 2009). These findings should not overlook the value of animal model studies of PD as they have significantly contributed to our understanding of disease etiology and have allowed for new treatments to be tested. However, current animal models of PD would more reliably translate into human studies if the progression of dopaminergic degeneration could be accurately simulated and if behavioral tests were to examine more subtle motor symptoms (Potashkin et. al., 2011).

In addition to the controversy regarding animal models, concerns have also been raised as to the adverse effects that may occur from elevated serum urate levels. Hyperuricemia, which refers to the buildup of uric acid in the blood, is the primary cause of gouty arthritis and has been associated with other cardiovascular, renal, and metabolic disorders and conditions (Crotty et. al., 2017). Furthermore, studies have indicated that uric acid only exhibits antioxidant properties in a hydrophilic environment. This poses a significant limitation to its therapeutic potential as uric acid is capable of becoming a pro-oxidant by reacting with other oxidants to form radicals. Under these circumstances, urate would paradoxically contribute to the very problem it was proposed to solve (Sautin & Johnson, 2010). Therefore, there remains a need to determine the optimum threshold of uric acid concentrations that will improve PD treatment without producing the previously mentioned negative side effects. Lastly, as previously stated, urate's antioxidant properties have been suggested to be involved in a shared mechanism of the pathophysiology of neurodegenerative diseases (Cipriani et al.,2011). While it may be a suitable biomarker for the diagnosis and prognosis of early PD, uric acid alone cannot distinguish between PD and non-PD diagnoses (Yu et. al., 2017).

The combined findings presented in this review support the notion that urate exhibits strong potential as a biomarker and target of therapeutic treatment for Parkinson's Disease. Numerous studies have provided evidence for urate's role in neuroprotection. The most significant findings revealed (1.) an inverse correlation between serum urate levels and the risk of developing PD as well as (2.) its capacity to prevent dopaminergic cell death. Although the evidence is compelling, shortcomings of current studies include the limitations of using animal models of PD as well as the adverse health effects of excess uric acid. To address these drawbacks, future studies should aim to more accurately replicate symptoms of PD in animal models as well as investigate the dose-response relationship for urate levels in PD as to determine the optimum concentration. Despite the inevitable flaws of current studies on uric acid and PD, urate remains as a promising candidate for the diagnosis and treatment of Parkinson's Disease.