Screen for Novel Glucocerebrosidase-Interacting Parkinson's Genes

Objective/Rationale:
Our goal is to discover new genes that lead to Parkinson’s disease.  Most of the known causes of Parkinson’s disease are rare and account for a minority of patients. However, it was recently found that up to 15% of patients with Parkinson’s disease have a predisposing mutation in a gene called glucocerebrosidase (GBA). We will use an animal model to screen and identify new genes that interact with GBA to cause Parkinson’s.

Project Description:
We will make zebrafish which carry a mutant GBA gene, using both knock-out and transgenic approaches.  We will then characterize these stable lines, and examine them for characteristic Parkinson’s disease pathology in the nervous system, as well as for motor problems (such as difficulty swimming) that are typical in Parkinson’s disease.  Using these mutant GBA zebrafish, we will perform a large-scale screen for other genes that interact with GBA that lead to Parkinson’s disease.  

Relevance to Diagnosis/Treatment of Parkinson’s Disease:        
Our project helps to develop a small vertebrate animal model for Parkinson’s disease.  Our work will address the role of GBA in Parkinson’s disease and the timing of when GBA leads to degeneration of neurons in the nervous system.  We expect that our screen will identify novel genes that help us understand how Parkinson’s disease occurs. Further, these novel genes may account for a larger percentage of patients affected by Parkinson’s.

Anticipated Outcome:
A short, lay-oriented description of what you expect to learn by carrying out the work. Approximately 75 words
This project will include detailed investigations into the mechanism by which GBA leads to Parkinson’s disease.  With this study we expect to identify multiple genes with previously unrecognized roles in Parkinson’s disease.  We plan to characterize how these genes lead to death of dopamine neurons. Importantly, the screen may identify genes that by themselves have important roles in leading to Parkinson’s disease and are as yet unrecognized.