Objective/Rationale:
Mutations in the LRRK2 gene unambiguously associate with the development of late-onset Parkinson’s disease that mimics clinical and neurochemical features typical of the disease. Our work has demonstrated that the most common mutations found in PD cases activate the enzymatic activity of the LRRK2 protein in test tubes. This project will determine whether this enzymatic activity is required to recapitulate the neurodegeneration found in PD cases in pre-clinical models of disease.
Project Description:
In order to move research from a test-tube into animal models, we will first develop novel technology capable of transferring the PD-associated LRRK2 protein into regions of the mouse brain that correspond to regions of the human brain that degenerate in PD. The LRRK2 gene encodes a protein of exceptional size that contains multiple regions all required for proper function. The sheer size of the protein prevents the use of the most commons methodologies used in neuroscience research. In this project, we develop specialized viral transduction technology capitalizing on modified herpes-simplex virus and adenovirus vectors to move protein in an efficient and relevant manner into mouse brain. In addition, we utilize LRRK2 protein variants within these viral constructs that allow us to test the requirement of LRRK2 enzymatic activity in producing a neurodegenerative phenotype.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
LRRK2 enzymatic activity represents the first clear target in the field of neurodegeneration that is probably modifiable by small molecules, i.e. drugs. If our results demonstrate that LRRK2 enzymatic activity is required for neurodegeneration in animal models, full research efforts will be placed by our group as well as others around the world in finding drugs to inactivate the LRRK2 enzyme and potentially halt or slow PD-associated neurodegeneration in humans.
Anticipated Outcome:
Our work in test tubes clearly demonstrates that PD-associated mutations in LRRK2 change enzyme activity of the LRRK2 protein. This project seeks to determine whether these changes in enzyme activity directly cause neurodegeneration or whether the enzyme activity has little or no direct effect in producing a disease phenotype in animal models.