A Zebrafish Assay for Parkinson's Disease Drugs

We are developing an innovative model for Parkinson's disease using transgenic animals. The model is designed to rapidly screen thousands of potential small molecule drugs and to reduce the time it takes to test and validate new drugs. These animal embryos develop a group of tyrosine hydroxylase-positive dopaminergic neurons by one day after fertilization. These neurons can be made easily visible by transgenic incorporation of green fluorescent protein (GFP). The fluorescent embryos will be cultured in neurotoxins, such as MPTP, that are known to selectively destroy dopaminergic neurons. Damage to neurons can be measured based on a decrease in fluorescence. Molecules of known function, as well as novel molecules, will then be tested for their ability to protect neurons or promote new neuronal growth. Success in this endeavor can be accelerated for high throughput by using a fluorescent imager to quantify changes in fluorescence in a 96-well plate format, where animal embryos can live in culture media for several days. Molecules identified in this system have the potential to serve as novel drugs for the treatment of Parkinson's disease. Since current high throughput technologies that utilize cells or explants in culture may not reflect the true in vivo environment, this assay will represent a significant advance in drug discovery.