University of Dundee

Molecular mechanisms underlying Parkinson's disease

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]. 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 [1]. In recent studies we have started to explore how LRRK2 is regulated and have discovered several signalling components such as VPS35 [2] and Rab29 [3], strikingly controls LRRK2 pathway activity. We have recently identified a poorly studied protein phosphatase termed PPM1H that counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins [4].

The goal of this studentship is to dissect the molecular mechanism by which LRRK2 is regulated and work out how this is linked to Parkinson's disease. 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 important area medical research.

References

1. Alessi, D. R. and Sammler, E. (2018) LRRK2 kinase in Parkinson's disease. Science. 360, 36-37 {http://science.sciencemag.org/content/360/6384/36.long}

2. Mir, R., Tonelli, F., Lis, P., Macartney, T., Polinski, N. K., Martinez, T. N., Chou, M. Y., Howden, A. J. M., Konig, T., Hotzy, C., Milenkovic, I., Brucke, T., Zimprich, A., Sammler, E. and Alessi, D. R. (2018) The Parkinson's disease VPS35[D620N] mutation enhances LRRK2 mediated Rab protein phosphorylation in mouse and human. Biochem J {http://www.biochemj.org/content/475/11/1861.long}

3. Purlyte, E., Dhekne, H. S., Sarhan, A. R., Gomez, R., Lis, P., Wightman, M., Martinez, T. N., Tonelli, F., Pfeffer, S. R. and Alessi, D. R. (2018) Rab29 activation of the Parkinson's disease-associated LRRK2 kinase. Embo J. 37, 1-18 {http://emboj.embopress.org/content/37/1/1.long}

4. Berndsen, K., Lis, P., Yeshaw, W., Wawro, P.S. Nirujogi, R.S., Wightman, M., Macartney, T., Dorward, M., Knebel, A., Tonelli, F., Pfeffer, S.R. and Alessi, D.R. (2019) PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins-Submitted for Publication { https://www.biorxiv.org/content/10.1101/711176v1}

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.

Please send a CV with contact details of three referees to and a cover letter explaining why you have chosen to apply to MRC PPU to mrcppu-phd-admin@dundee.ac.uk. The closing date for applications is 15th February 2021 with shortlisting and interviews in March 2021. Application from overseas students are welcome.

 

Eligibility