Lead RVC Supervisor: Dr. Patrick A. Lewis and Dr. Helen Stolp 

Department: Comparative Biomedical Sciences  

Background, aims and objectives:

Mutations in Leucine Rich Repeat Kinase 2 (LRRK2) are the most common genetic cause of Parkinson’s disease (PD). This has made LRRK2 the focus of extensive investigation and drug discovery efforts over the past two decades. Despite these efforts, however, there are a number of key aspects of LRRK2 function, and dysfunction in disease, that we still don’t understand.  A standout example is the impact and consequence of the G2385R coding variant in the WD40 carboxy terminal domain of LRRK2. The G2385R variant is found in East Asian populations, where the arginine minor allele is present in approximately 2% of the population, meaning that a minimum of several hundred thousand individuals carry this in the heterozygous state. Despite the genetic burden presented by this variant, our understanding of how this coding change leads to increased risk if Parkinson’s is poor. The majority of disease causing (and highly penetrant) autosomal dominant variants in LRRK2 increase the kinase activity of the protein complex. Counterintuitively, G2385R has been reported to decrease the kinase activity of LRRK2. This is a potentially critical observation, with important translational implications as the majority of drug discovery efforts targeting LRRK2 seek to reduce kinase activity with small molecule inhibitors. As such, it is critical to gain a fuller understanding of what the G2385R variant does to LRRK2, and how this variant responds to small molecule targeting - which is the goal of this MRes project.  

The project will involve an exhaustive characterization of the cellular impact of LRRK2 biochemical and cellular function, building on our extensive track record of investigating LRRK2 biology, divided into the following two objectives. 

1. Biochemical characterization: kinase activity (measured across a panel of substrates), GTP binding and hydrolytic activity, protein/protein interactions and complex formation.
2. Cellular assessment: examine the response of LRRK2 to cellular stress, localisation within the cell, and capacity to regulate endolysosomal processes. 

The student will gain experience in advanced cellular models for Parkinson’s and functional assays for LRRK2, as well as being part of a world leading team of researchers investigating cellular dysfunction in this disease. 

References

1. Butterfield S, Herbst S, Lewis PA (2024) “Loss-of-function coding variants in the Ras of Complex Proteins/GTPase domain of Leucine Rich Repeat Kinase 2” bioRxiv 2024.12.07.627348https://doi.org/10.1101/2024.12.07.627348 
2. Zhu C, Herbst S, Lewis PA (2023) “Leucine Rich Repeat Kinase 2 at a glance” Journal of Cell Science 136: jcs259724 
3. Kluss J, Beilina A, Lewis PA, Cookson MR, Bonet-Ponce L (2022) “Lysosomal positioning regulates Rab10 phosphorylation at LRRK2-positive lysosomes” Proceedings of the National Academy of America 119: e2205492119 
4. Kluss J, Mazza M, Li Y, Manzoni C, Lewis PA, Cookson M, Mamais A (2021) “Preclinical modelling of chronic inhibition of the Parkinson’s disease associated kinase LRRK2 reveals altered function of the endolysosomal system in vivo” Molecular Neurodegeneration 16:17 

Requirements

Essential:

• Must meet our standard MRes entry requirements. 

Desirable:

• Experience of human cell culture methods and techniques.
• Experience of biochemical and imaging approaches to understanding cell biology (e.g. immunoblotting, confocal microscopy).
• Background or interest in neurodegenerative disorders 

Fees and Funding

This can be taken full-time or part-time (12months FTE) project commencing in October 2025, based at RVC's Camden campus. 

Partially funded: e.g. the lab will be covering the project costs, with the MRes student expected to meet the course fees and their living expenses.

Please note that EU/EEA and Swiss national students may no longer be eligible for the “Home” rate of tuition fees, dependent on personal circumstances (including immigration status and residence history in the UK) and UK government rules which are currently being developed. For up-to-date information on fees for EU/EEA and Swiss national students following Brexit please see our fees and funding page. 

How to Apply

For more information on the application process and English Language requirements see How to Apply. 

Deadline: 04/04/2025

Interviews will take place remotely (Teams, Zoom etc) within 4 weeks of the closing date. 

We welcome informal enquiries - these should be directed to plewis@rvc.ac.uk