Molecular and Cellular Mechanisms of Parkinson's Disease

There are two major challenges facing the Parkinson’s disease (PD) research community. The first challenge is developing a disease-modifying therapy that will slow or stop PD progression in its early stages. To achieve this goal, we need to have a better grasp of what causes PD. The cardinal motor symptoms of PD – bradykinesia and rigidity – are attributable to the degeneration of dopaminergic neurons in a small region of the brain called the substantial nigra pars compacta (SNc). The degeneration of these neurons is linked to the failure of their powerplants – mitochondria – and the accumulation of misfolded forms of a protein called alpha-synuclein. Our JPB funded studies have shown how mitochondrial powerplants are regulated, leading to the identification of drugs that lessen their stress and might slow disease progression. Moreover, we have shown that damage to a critical part of the mitochondrial powerplant is sufficient to cause staged, human-like parkinsonism in mice. A primary goal of our renewal application is to rigorously define the steps leading to degeneration of dopaminergic neurons in this new model of PD (called the MCI-Park model) with the conviction that doing so will translate into possible disease-modifying therapies. Our preliminary studies also have uncovered a potential synergy between mitochondria and misfolded alpha-synuclein. We plan to rigorously pursue this clue to identify strategies for slowing disease progression. The other challenge facing the PD community is the development of better symptomatic therapies. The core symptomatic therapies for PD patients have not fundamentally changed in 50 years. To achieve this goal, we need a better understanding of how and why brain circuits stop working properly as PD progresses. A significant obstacle to this effort has been the lack of animal models that manifest a clearly defined prodromal period before the appearance of gross motor deficits. A substantial step forward in this effort has been the development of the MCI-Park mouse model with its human-like staging of pathology, which includes a well-defined prodromal state. Not only does this model exhibit the progressive motor disability seen in PD patients, it surprisingly manifests a PD-like sleep disturbance. The second primary goal of our JPB proposal is to take advantage of the MCI-Park model to rigorously characterize how brain circuits controlling movement and sleep become dysfunctional as PD progresses from prodromal to parkinsonian states. This model also will be used to understand why levodopa treatment can produce debilitating dyskinesia. Understanding what drives abnormal brain activity in PD should provide us with new therapeutic options for patients. Indeed, our JPB-funded studies have identified a novel gene therapy that could effectively boost the symptomatic benefit of levodopa treatment in late-stage PD patients, as well as pharmacotherapies that lessen LID severity. By taking advantage of the latest technology and other members of the JPB PD consortium, the studies proposed should provide fundamental new insights into what causes neurodegeneration in PD, how this degeneration triggers brain dysfunction, how we can slow or reverse the course of the disease, and how we can more effectively alleviate symptoms.