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Molecular mechanisms underlying Parkinson's disease

  • Full or part time
    Prof Dario Alessi
  • Application Deadline
    Sunday, December 01, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

About This PhD Project

Project Description

There is great need for improved understanding of the mechanisms underlying Parkinson’s disease, to help with the development of new drugs that slow or even halt progression of the disease. The discovery that hyper-activating mutations in a protein kinase termed LRRK2 causes Parkinson’s, offers the prospect of new, potentially disease-modifying treatments [1]. Recent advances point towards LRRK2 controlling autophagy and lysosome function by phosphorylating selected Rab GTPase proteins and regulating their ability to bind effector proteins [1]. Recently, we started to explore how LRRK2 is regulated, and discovered several signalling components such as VPS35 [2] and Rab29 [3] that control LRRK2 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 how this is linked to Parkinson's disease. This project would also offer opportunities to collaborate with pharmaceutical companies as well as clinicians 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.

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- . The closing date for applications is December 1st 2019 with interviews in January 2020.

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}

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