Grant: Project Grant

It has been 53 years since the introduction of dopamine replacement therapy for Parkinson disease (PD). It remains the gold standard of clinical care but does not stop disease progression. Sadly, we do not yet have any cause-directed treatment options for our patients. Parkinson's is considered a complex disease in which both genetic risk and an environmental factor (or several) are required for disease initiation. The identity of these 'environmental hits' remains unknown. We have made critical discoveries over the last three years linking the environment and genetics in brain health in our model systems. Mutations in the LRRK2 gene increase the risk for PD; however, in itself a LRRK2 mutation rarely causes disease, suggesting that a second factor is required. We hypothesize that the second hit is environmental, specifically, microbial in nature. This is based on our finding of a critical role for LRRK2 in the immune system. We found that LRRK2 protects nerve cells from damages during a viral brain infection. Furthermore, we discovered a second PD-linked gene that also protects the brain during the course of an infection. The goals of the studies proposed in our application are to: 1) identify how these two genes act in an integrated response to protect the body and brain from infection; and 2) test a new understanding of PD development. There is growing recognition of the role of inflammation and the immune system in PD and related neurodegenerative diseases including Alzheimer's. These studies will inform current drug trials (note, LRRK2 is the lead therapeutic molecule for PD) and have the possibility to open an entirely new field of targets for drug discovery that are rooted in the immune response. The results of our work will have concrete impacts on the translation of health research for better clinical outcomes for Canadians with Parkinson's.