Regulation of LRRK2: Identifying vulnerabilities for Parkinson's Disease therapeutics

Parkinson’s Disease (PD) is the second most prevalent neurodegenerative disease, affecting ~10 million people worldwide. One of the most commonly mutated genes in PD codes for Leucine Rich Repeat Kinase 2 (LRRK2). Autosomal dominant mutations in LRRK2 cause familial PD, while mutations in LRRK2 are risk factors for sporadic PD and increased activity of LRRK2’s kinase has been linked to the sporadic form of the disease as well. This has made LRRK2 the main actionable target for PD therapeutics.
LRRK2 is a large protein with multiple domains, including both a kinase, which phosphorylates membrane-associated Rabs, and a Ras-like GTPase. The bulk of LRRK2 exists in the cytosol in an autoinhibited state and the protein is recruited to membranes, where its substrates are found. While we are beginning to understand LRRK2’s recruitment, how the protein becomes activated and is generally regulated remains a mystery. We are using structural biology (cryo-EM), single-molecule biophysics, chemistry, biochemistry, and cell biology, to understand the LRRK2’s function and mechanism, and how these are affected by PD-linked mutations. Our goal is to use these fundamental insights into LRRK2 to discover new vulnerabilities that can be exploited for PD therapeutics.