Objective/Rationale:
Since the identification of a number of Parkinson’s disease genes in humans, much effort has been spent at developing pre-clinical models of the disease. However, most genetic pre-clinical models have been disappointing because the mutations do not usually lead to the death of dopamine-containing neurons, as is seen in humans. However, these models may help to identify early symptoms of Parkinson’s disease that appear prior to cell death. In the present project, our main goal will be to evaluate whether an early phenotype common to many Parkinson’s disease genetic models is a perturbation of the function of the dopamine transporter, a protein that works to recycle dopamine after its release in the brain.
Project Description:
We propose to compare dopamine transporter (DAT) function in four different genetic pre-clinical models of Parkinson’s disease. We will compare models in which the genes Parkin, DJ-1 and Pink1 are genetically inactivated. We will also use a model expressing a mutant form of the protein LRRK2. We will first use a technique called cyclic voltammetry to monitor the time course of dopamine accumulation in the pre-clinical models. We will also validate our functional results with direct measurement of DAT levels and localization. Our main goal will be to determine whether DAT levels or DAT function is perturbed in all or just a subset of these models.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The present project may lead to a better understanding of some of the early brain dysfunctions that accompany Parkinson’s disease. If we can identify dopamine transporter dysfunctions that appear early in the disease, prior to the onset of neuronal cell death, this may eventually lead to new strategies for early diagnosis and could facilitate the implementation of therapies that aim to prevent neuronal loss.
Anticipated Outcome:
If our main goals are reached, we will be able to conclude as to the generality of dopamine transporter dysfunctions in genetic pre-clinical models of Parkinson’s disease. We will also be able to obtain initial information as to the major reason for dopamine transporter dysfunction, such as altered expression or cellular localization. This will put us in a favorable position to test subsequently our main hypothesis in humans.