This grant builds upon the research from a prior grant: Purine Biomarkers of LRRK2 PD
Objective/Rationale:
Uric acid is a chemical produced naturally in the human body. In this project, we aim to investigate whether uric acid is an antioxidant capable of reducing the risk of Parkinson's disease (PD), and in particular, its inherited form caused by a change -- mutation -- in the gene for leucine-rich repeat kinase 2 (LRRK2), the greatest known genetic contributor to PD. In this study, we will use nerve cells derived from induced pluripotent stem cells (iPSCs), which are created by reprogramming mature adult cells from people with PD. Our study will explain why these nerve cells degenerate, and it will also test the neuroprotective potential of uric acid and the Nrf2 antioxidant pathway, chemical reactions inside the cell in which uric acid participates.
Project Description:
We will use stem cells from Parkinson's Progression Markers Initiative (PPMI), our large-scale, international biomarker study. The cells from three groups of participants -- people who have PD without a known cause, people with inherited PD and healthy volunteers -- will be programmed to become dopamine-producing nerve cells. These cells will serve as a model system for testing uric acid's ability to protect nerve cells from damaging effects of LRRK2 mutations. Since we have previously shown that uric acid protects nerve cells indirectly by acting on astrocytes -- another type of brain cells -- we will grow the iPSC-derived nerve cells together with astrocytes. We will treat the cells with uric acid and then assess whether the treatment prevents or slows the development of PD-related changes in iPSC-derived dopamine-producing nerve cells. These changes include cell death caused by one or more of the following factors: inflammation, excess of toxic forms of oxygen in the cell, and dysfunction of mitochondria, cell's energy generators.
Relevance to Diagnosis/Treatment of Parkinson's Disease:
The results of this study may accelerate uric acid therapy as a disease-modifying treatment candidate for people with LRRK2 mutations, who are at increased risk of PD. As LRRK2-specific neuroprotective candidate drugs are being developed, the testing of a promising, low-risk, disease-modifying agent, such as uric acid, in people carrying a LRRK2 mutation but not diagnosed with Parkinson's may provide a timely proof-of-concept demonstration of the feasibility of such treatment.
Anticipated Outcome:
Earlier, we found that among people carrying a LRRK2 mutation, those diagnosed with PD have less uric acid in their blood than people without Parkinson's. In this study, we aim to validate, for the first time, the ability of uric acid to protect nerve cells from damaging effects of LRRK2 mutations in iPSC-derived dopamine-producing nerve cells. Given the antioxidant property of uric acid and its involvement in the Nrf2 antioxidant pathway, it is likely to be therapeutic in LRRK2-associated inherited PD.