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 consortium (Drs. Greengard, Dawson, Sulzer and Lindquist) and a member of the Diabetes consortium (Dr. Spiegleman). Our second aim is to characterize the striatal mechanisms underlying LID. Our grasp of these mechanisms has significantly improved in the last award period and we are poised to make significant new discoveries. Two related lines of study will be pursued. First, we will characterize changes in the wiring of the striatum that occur after dopamine is lost and then restored with levodopa therapy. One of the fundamental insights during the last award period was that these changes are profound and are strongly correlated with symptoms. We have put in place a powerful new technology to allow these experiments to be done with an unprecedented level of precision. Second, we will continue our investigation of how the mechanisms controlling the strength of synaptic connections in the striatum goes awry following the loss of dopamine and then in the LID state. This line of study in the last award period led to the discovery that an M4PAM alleviated LID. These studies will be conducted in collaboration with members of the PD consortium (Drs. Greengard and Kaplitt) as well as a member of the Alzheimer’s disease consortium (Dr. Barres). We are confident that pursuit of these two aims will bring us closer to our broader goal: to develop new and powerful therapies that will improve the lives of PD patients.
|Effective start/end date||9/1/15 → 10/31/19|
- JPB Foundation (Grant #470)
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