Study Rationale: Genetic mutations that lead to the activation of the enzyme LRRK2 are a major cause of inherited Parkinson's disease (PD). Combining the expertise of our four laboratories, we will perform state-of-the art, collaborative experiments to unravel the biological mechanisms controlled by LRRK2 and to determine how LRRK2 activation is linked to PD. In particular, we aim to decipher how LRRK2 is switched on by cellular dysfunction and how it targets enzymes known as Rabs, triggering a cascade of downstream biological events. Our goal is to gain a better understanding of LRRK2-driven PD, providing foundations for the development of future therapies.
Hypothesis: We hypothesize that deciphering how the activity of LRRK2 is controlled and how it affects three major cellular structures implicated in PD — cilia, lysosomes and mitochondria — will facilitate our understanding of PD pathology in a manner that will improve future diagnosis and treatment.
Study Design: Our goal is to use a combination of state-of-the-art approaches to better understand how LRRK2 is activated and how LRRK2 impinges on the biology of primary cilia, lysosomes and mitochondria in the brain and other tissues. We will use mass spectrometry, microscopy, preclinical models and new methods we are developing to rapidly isolate lysosomes and mitochondria, allowing us to better define how these structures are impacted by PD-associated LRRK2 mutations. We also aim to ensure that our findings are independently replicated and validated by several team members prior to publication, to safeguard that our findings will stand the test of time.
Impact on Diagnosis/Treatment of Parkinson’s disease: Our findings will provide new and fundamental information related to the origin and progression of PD. Such information can improve diagnosis, optimize treatments and hopefully facilitate prevention of PD in the future.
Next Steps for Development: We will use our ties to MJFF and to leading clinical and pharmaceutical researchers to ensure that our research opens new opportunities to better understand and treat PD. We will discuss our data openly and contribute our expertise and emerging knowledge to aid with the development of future PD treatments.