Molecular and Cellular Mechanisms of Parkinson's Disease

There are two major unmet needs in Parkinson’s disease (PD) that we propose to address. First, there is no proven strategy for preventing or slowing PD progression. The best hope for the development of a neuroprotective therapy lies in studies aimed at identifying the mechanisms governing selective neuronal dysfunction and death in PD. Second, in the later stages of the disease there is no proven strategy for ameliorating the psychomotor side-effects of palliative levodopa treatment. Levodopa induced dyskinesia (LID) diminish the quality of patient life and limit the symptomatic benefit of levodopa treatment. Ameliorating LIDs should come from a better understanding of the striatal adaptations that are responsible for their induction. In the last three years, our JPB funded group has made great progress toward these two goals. Based upon our work, NIH funded a 5-year, $23M, 58 center Phase III clinical trial in North America to determine if isradipine will slow disease progression in early stage PD patients. Work in review now shows that a novel drug – a M4 muscarinic receptor positive allosteric modulator (M4PAM) –alleviates LID in mouse models, pointing to a potential new therapy. In this renewal application, we propose to build upon our past successes to pursue new therapeutic options. Our first aim is to better characterize the mechanisms governing selective neuronal dysfunction and death in PD. Understanding why some neurons die should reveal the causes of PD and others don’t. Three inter-related lines of study will be pursued in at-risk substantia nigra dopaminergic neurons. First, we will continue our examination of the link between calcium, dopamine and mitochondrial oxidant stress. Second, we will examine how substantia nigra dopaminergic neurons change in a new mouse model of human brain aging. Third, we will examine how inflammation affects at-risk dopaminergic neurons. These studies will be pursued in collaboration with members of the PD consor