Our ability to develop useful treatments for neurodegenerative diseases such as Parkinson's disease is hampered by our lack of understanding of the etiology of these disorders. One way of addressing the problem is to develop animal models of the disease and to use these to test hypotheses concerning the origin and progression of the neural degeneration. The ability to test these hypotheses and to create new models for Parkinson's would be greatly facilitated by the ability to generate mice that express a selected gene exclusively in dopaminergic neurons. Here we propose to produce transgenic mice permitting the regulated expression of genes in a subset of dopaminergic neurons. Specifically, we will construct a transgenic mouse line (""""""""the dopaminergic mouse"""""""") using the promoter for the dopamine transporter (DAT) to drive the expression of the tetracycline transactivator. When mated to a distinct transgenic line containing a candidate gene whose transcription is regulated by the tetracycline operator, the resulting offspring should express the candidate gene in dopaminergic neurons in the presence of the inducer, tetracycline. The availability of mice that inducibly express genes in dopaminergic neurons should help neuroscientists tackle Parkinson's disease by facilitating the production of new models of this disease. As additional genetic loci related to the origin or progression of Parkinson's emerge from our improved understanding of the human genome, these genes or altered versions of these genes can be specifically re-inserted into dopaminergic neurons to assess their effects. Use of the dopaminergic mouse would be superior to currently available systems, which express genes in larger collections of cells. Through these efforts, we hope to create a genetic tool that will accelerate the development of new therapeutics for the patient with Parkinson's disease.
