Objective/Rationale:
Neurons in the striatum play a critical role in the fine control of movements. The primary loss of dopamine neurons in Parkinson's Disease induces dramatic secondary changes in the morphology and function of the striatal neurons due to altered regulation of calcium ion concentrations within these cells. CaMKII is an abundant and important neuronal protein that responds to changes of intracellular calcium ion concentrations that is abnormally activated following dopamine depletion. Our objective is to determine whether correction of CaMKII regulation following dopamine depletion is a viable strategy to help ameliorate symptoms of Parkinson's disease.
Project Description:
We will use two different genetic strategies to normalize (i.e., inhibit) striatal CaMKII activity following dopamine depletion in mice. First, we will replace a critical Thr residue in CaMKII with Ala, preventing the sustained activation of the enzyme following dopamine depletion. Second, we will reversibly express in the striatum an artificial CaMKII inhibitor protein that permits us to reversibly control CaMKII activity at times of our choosing. Dopamine depletion will be induced in these mice, as well as normal wild type controls, and the mice will then be injected with levodopa to mimic the well established Parkinson’s Disease treatment paradigms. The impact of these genetic manipulations on the behavioral consequences of dopamine depletion and levodopa injections will be established.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If one or both of our genetic strategies ameliorate the behavioral effects of dopamine depletion or the levodopa injections, this will suggest that CaMKII is a viable candidate for development of new therapeutic interventions. We anticipate that such interventions will help manage dyskinesias and other debilitating side effects associated with long-term dopamine replacement therapy of Parkinson's Disease or may provide adjunct approaches to prolong the efficacy of dopamine replacement therapy.
Anticipated Outcome:
In summary, the outcome of these studies will determine whether the inhibition of CaMKII can prevent or compensate for key behavioral phenotypes associated with striatal dopamine depletion and chronic levodopa-based therapies.