Mapping the Modulatory Landscape Governing Striatal Dopamine Signaling and Its Dysregulation in Parkinson’s Disease

Study Rationale:
Nerve cells that produce the brain chemical dopamine die in people with Parkinson’s disease. These dopamine-producing nerve cells extend very long and thin fibers called axons that release dopamine from thousands of different points, sending signals to other nerve cells in a brain area called the striatum. We have found that many different types of cells and molecules in the striatum can directly control how dopamine is released, but we haven’t yet discovered which ones are the most important and how they are affected in Parkinson’s. If we could better understand this cooperation between striatum and the release of dopamine from axons, then we could provide new knowledge toward ways to restore normal function.   

Hypothesis:
We think that other molecules in the striatum play a very important role in controlling the release of dopamine, particularly for the types of dopamine axons that are most vulnerable in Parkinson’s disease. We believe that this role is disrupted in the disease and could be targeted to rescue symptoms.

Study Design:
Our international team will combine cutting-edge research methods in mice and human cells that allow us to study the biology behind Parkinson’s disease. We will measure dopamine and other signaling molecules in different areas of the striatum, and work out what they do. This work will reveal the biological differences between vulnerable and resistant areas. We will use this knowledge to study the most promising molecules in mice that develop Parkinson’s and in cells from people with Parkinson’s, to then suggest new ways that might fix the problems with dopamine in the disease.

Impact on Diagnosis/Treatment of Parkinson’s Disease:
Our discoveries will provide knowledge that may help to find new ways of treating Parkinson’s using medicines that target the key signaling molecules in striatum that control dopamine release.

Next Steps for Development:
Next steps include testing how fixing problems with the most promising molecules can treat the symptoms of Parkinson’s in mice. We would work with doctors to test available medicines as well as with companies to develop new and better medicines.