Molecular and Cellular Mechanisms of Parkinson’s Disease

We propose to continue our ongoing effort to meet two major unmet medical needs of Parkinson’s disease (PD) patients. The first unmet need is a strategy for preventing or slowing PD progression. The ongoing, NIH sponsored, disease modification clinical trial with isradipine is a product of our JPB funding. Our near-term goal is to find complementary therapeutic strategies that decrease the vulnerability of at-risk dopaminergic neurons. The second unmet need is better symptomatic medications and a strategy for alleviating the side-effects of dopamine replacement therapy. The principal pharmacotherapy for PD patients – levodopa – has not changed in half a century. Although largely effective in the early stages of PD, the efficacy of levodopa wanes and as the dose needed to achieve relief rises, it induces dyskinesia. Therapies that complement levodopa, as well as strategies for preventing levodopa-induced dyskinesia (LID), will come from a better understanding of the basal ganglia adaptations driven by the progressive degeneration of neurons in PD. In the last three years, our JPB funded group has made great progress toward meeting these two unmet needs. In this renewal application, we propose to build on these discoveries to pursue our two overarching goals. To move us toward new disease modifying therapies, we propose to continue our investigation of mitochondrial function in at-risk dopaminergic neurons in mouse models. Many lines of evidence point to loss of mitochondrial oxidative phosphorylation as a driver of PD. We propose to study not only how neurons link their bioenergetic needs to mitochondrial function, but also to what the consequences of mitochondrial damage are to neuronal survival. In the last grant period, we discovered that loss of mitochondrial complex I (MCI) in dopaminergic neurons, mimicking the loss seen in PD patients, triggers a progressive, levodopa-responsive parkinsonism characterized by early axonal degeneration, as in humans. Our plan is to rigorously pursue characterization of this model and determinants of somatodendritic and axonal mitochondrial dysfunction. We also will test the hypothesis that one of the consequences of MCI damage and mitochondrial dysfunction is premature neuronal senescence; if this is the case, it would point to a completely novel restorative therapy for PD patients. These studies will be done in collaboration with Drs. Greengard, Dawson, Sulzer and Cuervo. To move us closer to new symptomatic therapies, we propose to continue our effort to characterize the cellular and molecular adaptations in the striatum of mouse PD and LID models. This work will be focused on recent work identifying purinergic and cholinergic signaling as key determinants of PD symptoms and LID. We also propose to broaden our scope to include study of substantia nigra in the progressive model of PD created by disruption of MCI in dopaminergic neurons. In this model, the core motor symptom of PD – bradykinesia – does not appear until dopaminergic markers are lost in the substantia nigra, well after they are lost in the striatum. If our inferences from this model are correct, it will fundamentally change current thinking about the network determinants of PD symptoms and how new symptomatic therapies should be targeted. These studies will be done in collaboration with Drs. Greengard, Sulzer and Kaplitt. These collaborative studies address fundamental questions in the PD field and are natural extensions of our previously JPB funded work.