There is great need for improved understanding of the mechanistic biology underlying Parkinson’s disease. Such knowledge will help with development of new drugs that slow or even halt the progression of the disease. The discovery that hyper-activating mutations in a protein kinase termed LRRK2 causes Parkinson’s, offers the prospect of elaborating new, potentially disease-modifying treatments (1, 2). Recent advances point towards LRRK2 controlling autophagy and lysosome function by phosphorylating a group of Rab GTPase proteins and regulating their ability to bind cognate effector proteins (3). We have explored how LRRK2 is regulated and discovered several signalling components such as VPS35 (4), Rab29 (5, 6), and other Rabs (7) that strikingly controls LRRK2 pathway activity. We have identified a poorly studied protein phosphatase termed PPM1H that counteracts LRRK2 signalling by selectively dephosphorylating Rab proteins (8).

Much evidence suggests that elevation of the LRRK2 pathway leads to lysosome dysfunction. We have recently identified a new downstream component of the LRRK2 pathway termed TMEM55B that may function as an E3 ligase that is located on the lysosome (9). The goal of this studentship is to dissect the molecular mechanism by which LRRK2 pathway regulates TMEM55B and the role that this has on controlling Parkinson’s relevant lysosome dysfunction. This could lead to new knowledge to help us better treat and diagnose Parkinson’s disease that is driven by the LRRK2 pathway. This project will provide training expertise in the state-of-the-art biochemistry, molecular biology, cell signalling, mass spectrometry, data analysis, scientific collaboration as well as statistics, communication, written and oral presentation. This project would also offer opportunities to collaborate with pharmaceutical companies as well as clinician’s evaluating LRRK2 inhibitors for the treatment of Parkinson’s disease. The studentship provides an opportunity to gain valuable research experience in working at the forefront of an area medical research with great unmet medical need.

References

1. D. R. Alessi, E. Sammler, LRRK2 kinase in Parkinson's disease. Science360, 36-37 (2018).

2. A. F. Kalogeropulou et al., Impact of 100 LRRK2 variants linked to Parkinson's disease on kinase activity and microtubule binding. Biochem J 479, 1759-1783 (2022).

3. D. Waschbüsch et al., Structural Basis for Rab8a Recruitment of RILPL2 via LRRK2 Phosphorylation of Switch 2. Structure 28, 406-417.e406 (2020).

4. R. Mir et al., The Parkinson's disease VPS35[D620N] mutation enhances LRRK2-mediated Rab protein phosphorylation in mouse and human. The Biochemical journal475, 1861-1883 (2018).

5. E. Purlyte et al., Rab29 activation of the Parkinson's disease-associated LRRK2 kinase. EMBO J 37, 1-18 (2018).

6. H. Zhu, F. Tonelli, D. R. Alessi, J. Sun, Structural basis of human LRRK2 membrane recruitment and activation. bioRxiv, 2022.2004.2026.489605 (2022).

7. H. S. Dhekne et al., Genome-wide screen reveals Rab12 GTPase as a critical activator of pathogenic LRRK2 kinase. bioRxiv, 2023.2002.2017.529028 (2023).

8. K. Berndsen et al., PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins. eLife 8, e50416 (2019).

9. P. Pal et al., Parkinson’s VP535[D620N] mutation induces LRRK2 mediated lysosomal association of RILPL1 and TMEM55B. bioRxiv, 2023.2006.2007.544051 (2023).

At the MRC PPU, as well as the possibility of a PhD in one particular lab, we offer the possibility of two 4.5-month rotations in labs of their choice. A range of other projects from MRC PPU scientists are advertised on this website. Rotations provide valuable experience and help with deciding on the choice of PhD project and research group.