About the Project
~15 Mendelian inherited disease loci including PINK1 and Parkin provide important inroads to understand the molecular pathology of Parkinson’s disease (PD). This disease is linked to mitochondrial dysfunction whereby dopaminergic neurons succumb to neurodegeneration, largely explaining PD motor deficiencies. PINK1 is activated on the outer mitochondrial membrane in response to oxidative stress and this leads to the phosphorylation of ubiquitin and a ubiquitin-like domain in the Parkin E3 ligase. These phosphorylation events lead to Parkin activation promoting the ubiquitylation-dependent mitophagy.
However, it is not known how PINK1 is activated and what the relevant targets of Parkin are. Physiological analysis of this pathway is hampered by the absence of overt phenotypes in mouse models. Recent studies using C. elegans [3] showed that autophagy is compromised in pink-1 and parkin mutant worms and that defective mitochondria accumulate in those mutants.
We aim to:
1) Establish if human PINK1 and Parkin complement the corresponding C. elegans mutants and if conserved phosphorylation sites are essential in vivo.
2) Using established proteomics approaches we will identify proteins that interact with PINK1 and Parkin and unbiased phosphoproteomics to uncover novel PINK1 substrates.
3) We will explore the conservation of novel binding partners and substrates of PINK1/Parkin in midbrain dopaminergic neurons from human pluripotent stem cells.
In summary, our joint project will establish PINK1/Parkin regulated circuits in vivo and uncover conserved mechanisms of PINK1 activation and Parkin mediated protein degradation in human neurons.
How is the project collaborative?
The project will showcase and exploit the expertise of the three participating laboratories. The Gartner lab has established C. elegans nematode worm models to study dopaminergic neurodegeneration. The Muqit laboratory has expertise to study PINK1 and Parkin signalling and mitochondrial quality control. The student would be initially based in Dundee combining advanced C. elegans reverse genetics and proteomics approaches (Gartner and Muqit labs). Upon discovery of novel PINK1 components, the student would spend an appropriate period of time work in the Kunath lab to confirm the findings in midbrain dopaminergic neurons from human pluripotent stem cells.
Primary Supervisor - Professor Anton Gartner
Secondary Supervisor - Dr Tilo Kunath
Secondary Supervisor - Dr Miratul Muqit
Primary Host Research Centre - University of Dundee
Secondary Host Research Centre - MRC Centre for Regenerative Medicine (Edinburgh)
Funding Status of this Project - Competition Studentship (UK/EU)
Deadline for Application - Friday, 9 February, 2018
Research Area(s) - Parkinson’s disease
Funding Notes
This PhD project is part of a Dundee-Edinburgh Parkinson’s Research Initiative that brings together clinicians and scientists with expertise in movement disorders, genetics, cell signalling, regenerative medicine, drug discovery, health informatics and clinical trials to enhance our understanding of the mechanisms of Parkinson’s and exploit this knowledge to develop and evaluate novel therapies in the clinic. The PhD project will be based in either Dundee or Edinburgh, but will be highly collaborative with significant interaction with the co-supervisor at the partner University.
References
Mutations in C. elegans neuroligin-like glit-1, the apoptosis pathway and the calcium chaperone crt-1 increase dopaminergic neurodegeneration after 6-OHDA treatment. Sarah-Lena Offenburger, Elisabeth Jongsma, Anton Gartner bioRxiv 203067; doi: https://doi.org/10.1101/203067, accepted for Plos Genetics
6-OHDA-induced dopaminergic neurodegeneration in C. elegans is promoted by the engulfment pathway and inhibited by the transthyretin-related protein TTR-33. Sarah-Lena Offenburger, Xue Yan Ho, Theresa Tachie-Menson, Sean Coakley, Massimo A. Hilliard, Anton Gartner, bioRxiv 198606; doi: https://doi.org/10.1101/198606, accepted for Plos Genetics
Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Palikaras K, Lionaki E, Tavernarakis N. Nature. 2015 May 28;521(7553):525-8. doi: 10.1038/nature14300. Epub 2015 Apr 20.
Structure of PINK1 and mechanisms of Parkinson's disease-associated mutations. Kumar A, Tamjar J, Waddell AD, Woodroof HI, Raimi OG, Shaw AM, Peggie M, Muqit MM, van Aalten DM. Elife. 2017 Oct 5;6. pii: e29985. doi: 10.7554/eLife.29985.
Parkinson's disease induced pluripotent stem cells with triplication of the α-synuclein locus. Devine, M. J., Ryten, M., Vodicka, P., Thomson, A. J., Burdon, T., Houlden, H., Cavaleri, F., Nagano, M., Drummond, N. J., Taanman, J. W., Schapira, A. H., Gwinn, K., Hardy, J., Lewis, P. A. and Kunath T. Nat Commun. 2011 2: 440.
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