Striatal determinants of Parkinson's disease progression

Parkinson’s disease (PD) has a long (5-20 years) prodromal phase that precedes difficulty in moving, rigidity, and tremor, which lead to clinical diagnosis. What drives the disease forward during this long prodromal period is not understood. Filling this gap could lead to a therapy that slows or stops progression to the clinical stage. A breakthrough in the effort has come with the development of the MCI-Park mouse model of PD. Unlike models used for the last 50 years, the MCI-Park mouse manifests a clear prodromal phase, much like human PD. Moreover, as in humans with PD, the earliest pathology in the model is in the axons of dopaminergic neurons that reach the striatum. We plan to take advantage of this unique opportunity to test the hypothesis that the early loss of dopamine release in the striatum is the lynchpin of the disease, resulting in a cascading set of changes in brain circuits that ultimately results in the neurodegeneration responsible for clinical parkinsonism. The proposed project incorporates an array of cutting-edge optical, electrophysiological, chemogenetic, anatomical, and behavioral approaches. If our innovative idea is correct, it would be transformative and help properly focus many lines of research that are underway, ranging from transplant therapies to the development of new disease-modifying drugs.