University of Dundee

CSC - 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 and Rab29 [2], 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 [3].

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 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 experience in working at the forefront of an important area medical research. 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.

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. 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}

3. 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}