Validation of Enzymatic Activity and Neuropathology in G2019S LRRK2-induced Dopaminergic Neurodegeneration in a Pre-clinical Model of Parkinson's Disease

Objective/Rationale: 
Mutations in the LRRK2 gene are a common cause of familial and sporadic Parkinson’s disease. Familial LRRK2 mutations induce neuronal toxicity in vitro. Reliable pre-clinical models of LRRK2-induced neurodegeneration do not currently exist. We have recently developed a pre-clinical model of G2019S mutant LRRK2-induced dopaminergic neurodegeneration by viral-mediated gene transfer. This project aims to further characterize the neuropathology induced by G2019S LRRK2 expression in such models and the contribution of enzymatic activity to neurodegeneration.
Project Description: 
We have developed a pre-clinical model of Parkinson’s disease by delivery of recombinant adenovirus expressing human LRRK2 to the substantia nigra. The expression of G2019S but not wild-type LRRK2 induces the progressive degeneration of nigrostriatal dopaminergic neurons. This model will be further characterized to determine the neuropathological, neurochemical and behavioral abnormalities associated with G2019S LRRK2 expression in the nigrostriatal pathway. LRRK2 can function as both a GTPase and kinase in vitro and both enzymatic activities contribute to G2019S LRRK2-induced toxicity of cultured neurons. Accordingly, we will determine the role of enzymatic activity for the pathological effects of G2019S LRRK2 in vivo. Our studies aim to understand the mechanism(s) of nigrostriatal dopaminergic neurodegeneration induced by G2019S mutant LRRK2 expression in a pre-clinical model.   
Relevance to Diagnosis/Treatment of Parkinson’s Disease:  
These studies will develop a pre-clinical model of Parkinson’s disease (PD) with dopaminergic neurodegeneration based upon the expression of the most common disease-associated LRRK2 mutation, G2019S. This model will help to understand the underlying mechanism of neurodegeneration induced by LRRK2 familial mutations and may provide a valuable pre-clinical model for evaluation of LRRK2-based therapeutics for treating PD.
Anticipated Outcome:
This project will determine the neuropathological abnormalities associated with G2019S LRRK2 and the contribution of enzymatic activity to the pathological effects of mutant LRRK2 in vivo. These studies will guide the development of future therapies based upon modulating LRRK2 enzymatic activity.
Note: This grant is based on initial studies from Dr. Romain Zufferey whose group developed essential tools needed to develop this model of PD.’