Uncovering Factors that Prevent Dopaminergic Neuronal Degeneration in a Novel C. elegans Model for Parkinson's Disease using a High-throughput Forward Genetics Approach

Objective/Rationale:
Our inability to slow down the progression of Parkinson’s disease (PD) reflects our incomplete knowledge of the molecular mechanisms that cause the selective death of dopaminergic (DA) neurons. Various animal models have been used to identify possible treatments, however, a truly representative model of the disease does not exist. We are introducing a new model for PD and a high-throughput approach to rapidly identify factors that can prevent neurodegeneration.

Project Description:
Our model is a mutant Caenorhabditis elegans (a worm) strain with a defect in an ion channel present on the surface of DA neurons. The defective channel, called TRP-4, results in a robust and progressive degeneration of DA neurons, triggered by excessive influx of calcium. This ‘Parkinsonian’ worm is the tool of our study. We believe that there is an entire network of genes that act downstream to execute dopaminergic neuronal death and our aim is to uncover them. We will use a high-throughput screening approach in combination with whole genome sequencing to rapidly identify factors that can prevent dopaminergic neuron degeneration.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Our study will provide a collection of factors that, when inactivated, prevent the death of dopaminergic neurons in our Parkinson’s model system. Such knowledge will help elucidate the molecular etiology of Parkinson’s while at the same time provide candidate targets that halt the progression of disease. The amenability to genetic manipulations of our model organism in conjunction with the state-of-the-art genetic tools our lab has developed can rapidly bring about our goal. The translational value of C. elegans research to human disease has been previously established; we therefore hope that our findings will be applicable to human patients.

Anticipated Outcome:
We expect by the end of this study to obtain a better understanding of the molecular causes of PD and possible ways to stop its progression. Specifically, we expect to identify genes that are responsible for executing dopaminergic neuronal degeneration. Analysis of the roles that these factors play in bringing about neuronal death will allow us to suggest therapeutic strategies that can halt the progression of PD in humans.