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MRC DiMeN Doctoral Training Partnership: The molecular cell biology jigsaw of Parkinson’s disease: bringing the pieces together


Project Description

This studentship results from an exciting new collaboration between two state-of-the-art laboratories at the University of Liverpool and the Sheffield Institute for Translational Neuroscience (SITraN) at the University of Sheffield, with a common interest in developing new insights into Parkinson’s disease (PD) that will open up new avenues for future therapies. This exciting programme of research will provide the trainee with an outstanding skills portfolio that will prepare them for a career in neurodegeneration research.

PD is the second most common neurodegenerative disorder affecting 2-3% of the population over the age of 65. Seventeen genes have been associated with increased PD risk to date (“PARK genes”). The big challenge in the field is to order these genes into common pathways that may underpin the pathology. Common themes are gradually emerging, linking several of the best characterised PD associated genes to two overarching processes: endo-lysosomal trafficking and mitophagy. Both these processes are areas of intense research in the two collaborating host laboratories.

Endo-lysosomal traffic is critical for the disposal of defective organelles and toxic protein aggregates by autophagy. PD is commonly associated with the accumulation of alpha-synuclein containing aggregates, called “Lewy bodies” in discrete regions of the brain. Mitophagy concerns the controlled disposal of defective mitochondria by selective autophagy. The resultant autophagosomes fuse with lysosomes where the degradation of enclosed material takes place. Failure to clear damaged mitochondria and aggregates in the dopaminergic neurons of the substantia nigra is thought to result in accumulation of reactive oxygen species and a calcium imbalance ultimately leading to cell death.

We are interested in the functional links between the best characterised PD associated genes (LRRK2, VPS35, PINK1 and Parkin). Parkin is a ubiquitin E3 ligase that is activated by PINK1 and plays a critical role in mitophagy. Interestingly, we have shown that Parkin can ubiquitylate VPS35, a protein involved in vesicular trafficking. VPS35 mutants cause mis-sorting of newly sythesised lysosomal enzymes and defects in lysosome biogenesis. A PD associated mutant form of VPS35 has been found to activate the LRRK2 kinase, one of the most commonly mutated genes associated with familial PD. The most prominent substrates of LRRK2 belong to the Rab family of small GTPases, key regulators of vesicular trafficking and VPS35 function.

The project will incorporate live and fixed cell imaging techniques and biochemical methods using model tissue culture cell systems. A proteomic component is anticipated and training in the preparation of samples for mass spectrometry as well as the analysis and interpretation of proteomic datasets will be provided. We will use CRISPR/Cas9 gene editing to generate isogenic cell lines that will allow for comparison between mutant and wild-type forms of PD associated genes. A component of the project will entail the use of dopaminergic neurons generated from neuronal precursor cells (NPCs) that can be derived from patient derived fibroblasts. This innovative system is advantageous compared with iPSC models as NPCs retain the epigenetic signatures associated with ageing.

Webpages of PIs:

http://pcwww.liv.ac.uk/~urbe/
http://pcwww.liv.ac.uk/~clague/

http://sitran.org/people/mortiboys/
https://www.sheffield.ac.uk/neuroscience/staff/mortiboys#tab00


Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Includes:
Stipend at national UKRI standard rate
Tuition fees
Research training and support grant (RTSG)
Travel allowance
Studentships commence: 1st October 2019.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website
Good luck!

References

Marcassa,E., Kallinos,A., Jardine,J., Rusilowicz-Jones,E.V., Martinez,A., Kuel,S., Islinger,M., Clague,M.J. and Urbé,S. (2018) Dual role of USP30 in controlling basal pexophagy and mitophagy. EMBO Reports, 19, e45595.

MacDonald,E., Brown,L., Selvais,A., Liu,H., Waring, T., Newman,D.T., Bithell,J., Grimes,D., Urbé,S., Clague,M.J. and Zech,T. HRS-WASH axis governs actin mediated endosomal recycling and cell invasion. (2018) J. Cell Biol. 217, 2549-2564.

Bell SM, Barnes K, Clemmens H, Al-Rafiah AR, Al-Ofi EA, Leech V, Bandmann O, Shaw PJ, Blackburn DJ, Ferraiuolo L, Mortiboys H.
Ursodeoxycholic Acid Improves Mitochondrial Function and Redistributes Drp1 in Fibroblasts from Patients with Either Sporadic or Familial Alzheimer's Disease. (2018) J Mol Biol.19;430(21):3942-3953.

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