Cellular Mechanism of LRRK2 in Health and Disease

Study Rationale:
Leucine Rich Repeat Kinase 2 (LRRK2), is the most commonly mutated gene in inherited forms of Parkinson’s disease (PD). The LRRK2 gene codes for a protein kinase, an enzyme that adds chemical groups to other proteins to change their activity inside cells. However, we currently do not understand how LRRK2 normally works and why its malfunction causes PD. Importantly, LRRK2 has also been shown to function abnormally in PD patients that have the sporadic form of the disease, making LRRK2 one of the most promising targets for drug development.

Hypothesis:
We recently discovered that chains of the LRRK2 protein can wrap around cellular highways called “microtubules.” Our work suggests that LRRK2 blocks the cellular machines that move on these highways. We will explore the idea that mutations in LRRK2 cause PD by acting as roadblocks that change the normal transport of chemical information inside cells. We will test additional ideas that arise from the experiments we perform.

Study Design:
Our collaborative team includes experts in cryo-electron microscopy (Cryo-EM), cryo-electron tomography (Cryo-ET), small molecule synthesis, proteomics, and single-molecule and live-cell imaging. We will use our expertise to solve structures of multiple conformations and variants of LRRK2 to manipulate these different pools of LRRK2 and understand their cellular functions. We will determine how LRRK2 binds to microtubules and affects microtubule-based motors. We will also identify the protein interaction landscape of LRRK2 and test emergent cellular hypotheses resulting from this work, including whether LRRK2 regulates the transport of chemical information on microtubules.

Impact on Diagnosis/Treatment of Parkinson’s Disease:
A major barrier to developing LRRK2-based PD therapy has been the lack of a blueprint of LRRK2’s three-dimensional shape, alone or interacting with other molecules it comes into contact with inside human cells. We expect our work will reveal what LRRK2 looks like, what it does in cells, and why its malfunction causes PD. Our work will be critical for the design of drugs targeting LRRK2.