My PD Story

Visualizing How LRRK2 Contributes to Parkinson’s

Several genetic variants have been identified that likely contribute to Parkinson’s disease (PD) progression. These variants typically alter the instructions for constructing proteins, the building blocks of the body.

Variants of the gene that create a protein called Leucine-Rich Repeat Kinase 2 (LRRK2) are found in 1-5% of all PD cases. Despite being the second most common PD-associated genetic variant, scientists are still unsure exactly how this altered LRRK2 protein causes or contributes to the disease biologically.

Tatyana Bodrug, PhD, a recipient of a Parkinson’s Foundation Postdoctoral Fellowship, will utilize a wide range of state-of-the-art microscopy and other visualization techniques to literally see how the LRRK2 protein acts in cells. By getting a clear picture of how LRRK2 interacts with other important cell processes, Dr. Bodrug hopes to advance the field toward more targeted and effective therapies.

Research suggests that LRRK2 plays a critical role in repairing lysosomes, the recycling centers of the cell whose dysfunction is closely linked to PD. Under the mentorship of Andres Leschziner, PhD, at Weill Cornell Medicine in New York City, Dr. Bodrug will first use a technology called cryo-electron microscopy (cryo-EM) to take incredibly zoomed-in, high-resolution images of LRRK2 as it interacts with lysosomes to see this biological process at a previously unmatched level.

“This integrative approach will reveal a deeply contextualized view of how LRRK2 is activated at the lysosome to better understand how mutations in LRRK2 lead to PD.” - Dr. Bodrug

This technology will also allow Dr. Bodrug to visualize what other proteins interact with LRRK2. Understanding the distinct biological components affected by LRRK2 could lead to new targets for PD treatment.

To investigate these components further, Dr. Bodrug will use a technique called dynamic mass photometry (dynamic-MP) to witness how LRRK2 associates with a group of proteins called “Rab” proteins. These Rab proteins are modified by LRRK2 and may themselves be involved in PD. This dynamic-MP technology allows individual LRRK2-Rab interaction events to be directly tracked in real time, an impressive technological achievement that is likely to advance the field.

By combining these various cutting-edge imaging procedures, Dr. Bodrug hopes to capture valuable insights into LRRK2 that could break new ground and lead to improved treatments of LRRK2-linked PD. Speaking on the impact of this fellowship, she said “Receiving this award allows me to more broadly explore the mechanisms that underlie Parkinson's disease. Our hope is that this will lead to a clearer understanding of the complexities involved in LRRK2-associated Parkinson's disease and better therapeutics.”

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