Studentship | Decoding a New Signalling Axis in Parkinson’s Disease

MRC Funded
Northwood
Project with

The challenge

Mutations in the kinase LRRK2 are one of the most common inherited causes of Parkinson’s disease, yet we still don’t fully understand how LRRK2 drives disease at the molecular level (1, 2). Our lab aims to change that, by uncovering how LRRK2 signalling is regulated, how it malfunctions in Parkinson’s disease, and how these insights can guide the discovery of new biomarkers and therapeutic targets.

The discovery

We have identified a previously unknown signalling pathway triggered by endolysosomal stress, a hallmark of many Parkinson’s disease models (3, 4). Mutations in LRRK2 and VPS35 cause cargo misrouting and abnormal recruitment of LRRK2 to stressed lysosomes, where it hyperphosphorylates a subset of Rab GTPases. These phosphorylated Rabs bind the effector RILPL1, which then interacts directly with the lysosomal membrane protein TMEM55B via a conserved TMEM55B Binding Motif (4).

We have recently solved the crystal structure of the TMEM55B–RILPL1 interactor complex, revealing the molecular details of this interaction for the first time. To probe its functional importance, we have developed two unique knock-in mouse models:

  1. A TMEM55B mutant unable to bind RILPL1
  2. A RILPL1 mutant unable to bind TMEM55B

The project

You will investigate how disrupting the TMEM55B–RILPL1 axis impacts lysosomal biology and Parkinson’s disease -relevant signalling. Using brain tissue and primary cells from these mouse models, you will perform lysosome immunoprecipitations (Lyso-IPs) followed by deep proteomic, lipidomic, and phosphoproteomic profiling using advanced mass spectrometry. You will analyse multi-omics datasets to map signalling changes, identify key effectors, and validate them through mechanistic cell biology experiments.

What you will gain

  • Hands-on training in cutting-edge mass spectrometry (proteomics, lipidomics, phosphoproteomics)
  • Expertise in primary cell isolation and culture from mouse models
  • Advanced techniques in lysosome biology, including LysoTag-IP
  • Multi-omics data analysis and interpretation skills
  • Experience designing and executing mechanistic follow-up experiments
  • Opportunities to collaborate with world-leading researchers, clinicians, and pharmaceutical partners
  • Engagement with people living with Parkinson’s disease to connect your research to patient impact

Why this matters

This is a unique chance to help unravel a completely new branch of the LRRK2 signalling network, one that could reshape our understanding of Parkinson’s disease and reveal entirely new therapeutic avenues. You’ll join a highly collaborative, internationally recognised research environment at the University of Dundee’s MRC-PPU, known for its pioneering work in protein phosphorylation and ubiquitylation biology.

If you’re passionate about discovery science with clear disease relevance and want to master an advanced, interdisciplinary skill set that’s in demand in both academia and industry this project offers a rare and exciting opportunity.

References

1. D. R. Alessi, S. R. Pfeffer, Leucine-Rich Repeat Kinases. Annu Rev Biochem 93, 261-287 (2024).

2. D. R. Alessi, E. Sammler, LRRK2 kinase in Parkinson's disease. Science 360, 36-37 (2018).

3. R. Mir, F. Tonelli, P. Lis, T. Macartney, N. K. Polinski, T. N. Martinez, M. Y. Chou, A. J. M. Howden, T. Konig, C. Hotzy, I. Milenkovic, T. Brucke, A. Zimprich, E. Sammler, D. R. Alessi, The Parkinson's disease VPS35[D620N] mutation enhances LRRK2-mediated Rab protein phosphorylation in mouse and human. Biochem J 475, 1861-1883 (2018).

4. P. Pal, M. Taylor, P. Y. Lam, F. Tonelli, C. A. Hecht, P. Lis, R. S. Nirujogi, T. K. Phung, W. M. Yeshaw, E. Jaimon, R. Fasimoye, E. A. Dickie, M. Wightman, T. Macartney, S. R. Pfeffer, D. R. Alessi, Parkinson's VPS35[D620N] mutation induces LRRK2-mediated lysosomal association of RILPL1 and TMEM55B. Sci Adv 9, eadj1205 (2023).

Application Procedure

To apply for any of our PhD projects, please complete the following application

APPLY NOW

When completing the application, we will ask you to upload your CV and a cover letter explaining why you have chosen to apply to MRC PPU.

The closing date for applications is 31st October 2025. Applications from overseas students are welcome.

If you have any questions or need to get in touch with us, please email us at mrcppu-phd-admin@dundee.ac.uk.