Parkinson’s disease is the second most common neurodegenerative disorder. The majority of cases are idiopathic, having no identifiable cause. Approximately 5-10% of cases are due to inherited genetic mutations that provide a gateway to understand the mechanistic causes of this disease. The overt symptoms of Parkinson’s disease are movement related and include shaking, rigidity, slowness of movement and difficulty with walking. These symptoms arise due to the death of dopaminergic neurons in the substantia nigra. About 70% of human protein-coding genes have homologs in zebrafish, thus allowing this model organism to provide a platform to fully elucidate and understand the mechanisms of these mutations. We are employing the CRISPR/Cas9 system to develop zebrafish models for the disease by altering zebrafish homologues of genes linked to the disease including LRRK2 (Leucine Rich Repeat Kinase 2) and PARK2. LRRK2 is a large multidomain protein with GTPase and kinase activity. The GTPase regulates kinase activity. We created mutations in the GTPase domain of LRRK2 as well as a single nucleotide change in the kinase domain. The single nucleotide change corresponds to the most commonly reported mutation of LRRK2, G2019S, which enhances the kinase activity of the protein. PARK2 is an E3 ubiquitin ligase and we have created a deletion mutation that is predicted to impair its activity. We are employing behavioral studies to screen through the various mutants and evaluate their locomotor defects. We will also analyze changes to dopaminergic neurons through staining with tyrosine hydroxylase. Zebrafish models would not only empower mechanistic and gene interaction studies, but enable behaviorally based small molecule screens to identify compounds that alleviate Parkinson’s related phenotypes.