Grant: Project Grant

Parkinson's disease (PD) affects 1 in 500 people in Canada; over 100,000 Canadians are living with PD today and ~ 6,600 new cases of PD are diagnosed each year in Canada. PD is the second most common neurodegenerative disorder after Alzheimer's disease. It results from the loss of cells in the brain that produce dopamine, a chemical that controls the body's movements. As dopamine decreases, tremors can develop, muscle movements become slower and more rigid, and reflexes become impaired contributing to a loss of balance. Tetrahydrobiopterin (BH4) is a molecule which is essential for the functioning of enzymes that produce dopamine and other brain chemicals. We recently uncovered another function of BH4 in the immune system by which it plays a role in T-cell activation by controlling mitochondria bioenergetics. This led us to ask whether BH4 might also have a role in controlling mitochondrial processes in the nervous system, as it is known that mitochondria play a role in the deterioration of nerve cells in neurodegenerative disease such as PD. Based on our first experiments, strongly supporting this hypothesis, we will investigate the role of BH4 in PD and examine whether increasing the production of BH4 can reduce the disease. Specifically, we will use genetic engineering to develop mouse models which either produce less or more GCH1, an enzyme that limits the production of BH4, specifically in their dopamine producing neurons. We will investigate if these mice indeed develop symptoms of PD, hence establishing a novel disease relevant model system, and whether known mouse models of PD show reduced PD due to increased BH4 production. Moreover, we will study the effects of BH4 in cells from PD patients to provide first evidence on the function of this pathway in human PD and demonstrate its therapeutic potential.