MSc by Research: Molecular mechanisms underlying Parkinson's disease


   School of Life Sciences

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  Prof Dario Alessi, Dr E Sammler  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

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). In recent studies we have started to explore how LRRK2 is regulated and have discovered several signalling components such as VPS35 (4), Rab29 (5, 6), and other Rabs (7) strikingly controls LRRK2 pathway activity. We have recently identified a poorly studied protein phosphatase termed PPM1H that counteracts LRRK2 signalling by selectively dephosphorylating Rab proteins (8, 9).  

The goal of this project 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 project provides an opportunity to gain valuable research experience in working at the forefront of an area medical research with great unmet medical need.  

Please see our website for further details on the programme:

Life Sciences MSc by Research MSc by Research (Postgraduate) : Study : University of Dundee

Please note before submitting your application that you must list your top three project choices in the Research Proposal section of the application form.

You apply for this course using our Direct Application System. Once you've signed up for an account you'll be asked to search for a course.

https://www.dundee.ac.uk/study/pgr/research-areas/life-sciences/

To find Life Science MSc by Research you should select the following options:

·  Course type: Research Postgraduate

·  Keyword: Life

When you complete your form, you should include your top 3 project choices, 2 letters of reference, uploaded under "Other Information" > "Supporting documents" and a personal statement. Failure to do so will delay your application.

Please note when submitting an application that we have the following deadline dates throughout the year:

September Starts - Application Deadline 1st May, Interview Date - Late June

January Starts - Application Deadline 1st Sep, Interview Date - Late October

May Starts - Application Deadline 1st Feb, Interview Date - Late March 

Biological Sciences (4)

References

References   
1. D. R. Alessi, E. Sammler, LRRK2 kinase in Parkinson's disease. Science 360, 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,  (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 journal 475, 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. E. G. Vides et al., A Feed-forward Pathway Drives LRRK2 kinase Membrane Recruitment and Apparent Activation. bioRxiv, 2022.2004.2025.489459 (2022). 
8. K. Berndsen, D. R. Alessi, Assay for quantifying PPM1H phosphatase activity towards LRRK2 phosphorylated Rab proteins and peptides using the Malachite Green method. Protocols.io dx.doi.org/10.17504/protocols.io.bustnwen,  (2021). 
9. K. Berndsen et al., PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins. eLife 8, e50416 (2019). 

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 About the Project