Development of a Zebrafish PD Drug Discovery Platform

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It is imperative that we develop rational and systematic approaches to drug discovery to treat Parkinson's and other neurological disorders. Rodent models are essential to this process, but they may not be the optimal starting place. The LRRK2 G2019S allele is the most common Parkinson's disease mutation and corresponding animal models have been developed in a variety of organisms. While the existing models are valuable, we engineered a zebrafish LRRK2 G2019S line that is a uniquely powerful starting place to accelerate PD therapeutics. The experimental flexibility of zebrafish including rapid gene targeting and unparalleled high-resolution functional brain imaging empowers studies of molecular, cellular and physiological mechanism of disease. However, the true power of zebrafish to promote PD research lies in the ability to conduct transformative experiments that cannot readily be done with other models. The ability to culture larvae in 96-well dishes and introduce test compounds via the water enables high throughput screening of small molecules using behavioral readouts. Tens of thousands of compounds can be assayed to identify potential therapeutic agents that can then be further refined to streamline the drug discovery pipeline. Our long-term goal is to perform such a screen to search for compounds that modulate Parkinsonian related behaviors using a zebrafish PD model. In order for this approach to be effective, behaviors that reflect those in patients must first be demonstrated in our LRRK2 G2019S mutant. The objectives of this study are to assay PD-related behaviors and dopaminergic populations in the zebrafish LRRK2 G2019S mutants to determine whether this model is a suitable substrate for high throughput chemical screens. If successful, this approach would go beyond identification of direct LRRK2 inhibitors and enable isolation of compounds that influence other processes to compensate for LRRK2 dysfunction.