Objective/Rationale:
Parkinson’s disease is caused by a selective loss of cells in the brain that produce the neurotransmitter dopamine. The major treatment for PD is Levodopa (L-Dopa) which gets metabolized to dopamine and thus compensates for the lack of the brain’s own dopamine. Over time, however, the efficiency of L-Dopa decreases and side effects including cognitive deficits and dyskinesia increase. This is thought to be due to adaptive changes in one type of dopamine recipient cell in the striatum. These cells express a dopamine receptor called the D1 dopamine receptor.
Project Description:
We found that an enzyme called CK2 is an important player in the signaling pathway that becomes turned on once the D1 dopamine receptor is activated by dopamine (or L-Dopa). It is therefore plausible that CK2 may also be involved in the onset and severity of the Parkinsonian symptom of akinesia as well as in the L-Dopa-induced side effects such as dyskinesia. We will study the role of CK2 by using mice with reduced amounts of CK2 and lesion the dopamine-producing cells in these animals, thus generating mice which will exhibit PD-like symptoms. We will then use well-established behavioral paradigms (cylinder test, AIM determination) as well as biochemical analysis to determine if these mice exhibit an altered response to dopaminergic drugs, and to acute and chronic L-Dopa.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If our experiments show that CK2 indeed modulates the mice’s response to L-Dopa, one could envisage developing a small molecule inhibitor for CK2 that are brain-permeable. It could be hypothesized that this drug when co-administered with L-Dopa may reduce the amount of L-Dopa necessary to achieve the desired akinetic effects. L-Dopa could then be given at a lower dose to patients and potentially thereby the onset of the major long-term side-effect, the L-Dopa-induced dyskinesia, could be delayed.
Anticipated Outcome:
We expect to observe that CK2 can act to modulate the animals’ behavior in response to amphetamine and to chronic and acute L-Dopa. We expect that in the mice where CK2 is reduced the amount of amphetamine needed for locomotor response will be lowered. Similarly, we would expect an anti-akinetic effect with lower doses of L-Dopa in the lesioned mice when CK2 levels are reduced.