Objective/Rationale:
Identification of mutations in the alpha-synuclein gene in a familial form of Parkinson’s disease, then the demonstration of alpha-synuclein containing pathological aggregations in the brains of the more common non-familial PD patients has triggered a significant research effort in the recent years. Nevertheless, we still do not know how the alpha-synuclein protein causes toxicity in the affected dopamine neurons. Thus, the present proposal will explore whether the interaction of alpha-synuclein and dopamine per se is the underlying reason why these neurons are most vulnerable to damage and dies early in Parkinson’s disease.
Project Description:
We will combine two very powerful genetic tools to address the question raised above. First, we will utilize transgenic mice that have a defect in storing dopamine in specialized vesicles. We know that this defect will cause abnormal handling of dopamine in these cells. Then, we will use recombinant viral vectors to deliver two types of genes in these dopamine neurons. One gene will express the human form of the alpha-synuclein gene while the other one will either be ineffective or it will inhibit dopamine synthesis in the cells. In this way we will have a well-controlled experiment to test the interaction of dopamine and synuclein as a causative factor in the degeneration of dopamine neurons.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If our hypothesis is correct, it would mean that we could target dopamine synthesis or storage mechanisms in the early phases of the disease and modify the progression by preventing the formation of damaging toxic protein complexes in the cells. This type of therapy could modify the disease so that the patients may be protected from entering into very debilitating end stage disease period where the quality of life is poor but instead remain as active and independent individuals who can continue a normal social life in the society.
Anticipated Outcome:
We will test directly if dopamine plays a critical role in formation of toxic protein aggregations that eventually kill the affected cells in the brain.