Identifying genetic solutions to motor defects in Parkinson's disease with C. elegans
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Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by the loss of dopamine neurons in the brain. This loss results in severe motor defects, such as the inability to initiate and transition between motor patterns like standing and walking. Whereas much research is focused on ways to prevent the death of dopamine neurons, less research has addressed how to enable motion after the death of dopamine neurons in late-stage PD. This is difficult to study in traditional rodent models because they quickly become immobile and die following ablation of dopamine neurons. The model nematode C. elegans offers an alternative model for late-stage PD. We modeled late-stage PD using a mutant worm with a deletion in the cat-2 gene. This gene is required to synthesize dopamine, as it encodes tyrosine hydroxylase, a catalase found in all animals (including humans). Without tyrosine hydroxylase, the cat-2 mutant cannot produce normal amounts of dopamine. In a manner that intriguingly mirrors human PD, the cat-2 mutant is capable of some motion, but becomes noticeably paralyzed when transitioning from swimming to crawling motor patterns. To search for ways to treat this model of late-stage PD, we randomly mutagenized cat-2 worms and screened for the animals with mutations that suppressed the swim-to-crawl paralysis (SCP). We screened enough animals to theoretically have tested a mutation in every gene of the genome. From our screen, we independently isolated five mutant strains with recovered ability to transition from swimming to crawling. These strains were then characterized for secondary phenotypes. Preliminary analysis of these phenotypes suggests that mutations were made in secondary dopaminergic pathways and serotonergic pathways. Ultimately whole genome sequencing of the mutant strains, as a means of identifying the suppressor mutation, will provide insight into how to better treat PD in humans.