Genetic mutations that lead to the activation of the enzyme LRRK2 are a major cause of inherited Parkinson's disease. We aim to combine the complementary expertise of our four research laboratories to perform fundamental, state-of-the-art experimentation to better comprehend the biology that is controlled by LRRK2. Our goal is to gain a much better understanding of LRRK2-driven Parkinson's disease, hopefully providing foundation the development of future therapies.
LRRK2 targets and modifies a set of enzymes known as Rab GTPases, triggering new biological events by creating new protein:protein interactions. We aim to decipher what controls the activity of LRRK2 and to explore, in precise molecular detail, how this enzyme affects three major cellular structures (cilia, lysosomes and mitochondria) implicated in Parkinson’s disease.
We showed that mutant LRRK2 triggers a series of molecular changes that cause new sets of proteins to interact. Our goal is to use a combination of state-of-the-art approaches to understand the consequences of these new interactions on the biology of three important subcellular compartments: primary cilia, lysosomes and mitochondria. We will use mass spectrometry, microscopy, mouse models and new methods to rapidly isolate lysosomes and mitochondria, which will allow high-resolution analysis of how these organelles are impacted by Parkinson’s disease-associated LRRK2 mutations, with a focus on brain cells. Several team members will independently replicate and validate our findings prior to publication.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Our findings will provide novel, fundamental information of relevance to understanding the origin and progression of Parkinson’s that we hope will lead to new ideas to better diagnose, treat and even prevent this malady in the future.
Next Steps for Development:
We will maintain strong ties with leading clinical and pharmaceutical researchers within the Parkinson’s field. We will discuss our data openly and do all we can to contribute our expertise and emerging research knowledge to aid with the development of future Parkinson’s treatments.