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MRC DiMeN Doctoral Training Partnership: Understanding proteotoxicity of alpha- and gamma-synuclein in neuronal C. elegans models of neurodegeneration


Project Description

Synucleopathies, such as Parkinson’s Disease (PD), are neurodegenerative diseases characterised by the accumulation of alpha-synuclein (asyn) aggregates into Lewy Bodies in neurons, leading to toxicity and cell death. PD affects more than 10 million individuals worldwide, yet treatment options remain sparse. Excitingly, the supervisors’ work recently identified two short segments (P1 and P2) in the N-terminal region of asyn that act as “master-controllers” driving aggregation. Deletion of these sequences prevents aggregation in vitro and protect C. elegans models of PD against proteotoxicity. Interestingly, a single point mutation in the P1 region also occurs in the related protein gamma synuclein (gsyn), which increases gsyn aggregation in an ALS patient cohort.

The finding of P1/P2 as a master-controller of asyn/gsyn aggregation has high potential for generation of small molecule compounds or biologics such as affimers to control aggregation by binding this region. The finding could transform our ability to control aggregation of intrinsically disordered proteins more widely, as they are involved in a range of neurodegenerative diseases as well as cancer.

This project will investigate the molecular mechanism by which P1 and P2 control aggregation in asyn and gsyn in vitro and in C. elegans models of PD and ALS. Creating site-specific mutations we will identify key residues in P1/P2 that enhance/reduce aggregation, and investigate aggregation and toxicity in dopaminergic and motor neurons in C. elegans throughout aging of the worm as well as in human neuronal cell lines. Success will then be taken forwards into mice models of PD/ALS through ongoing collaborations. Finally, we will explore the ability of affimers, that specifically target the P1/P2 regions, to prevent aggregation and toxicity in C. elegans and providing a translational opportunity for the development of therapeutic options.

We will express the human disease proteins in C. elegans dopaminergic and motor neurons, and investigate neuronal degeneration and function, aggregation and cross-seeding throughout aging of the worm. We will utilise confocal and lightsheet microscopy and behavioural assays linked to dopaminergic and motor neuron function, combined with biochemical assays of aggregation rates in vitro. We will raise affimers against these proteins and test their effect on asyn/gsyn aggregation in vitro and, in C. elegans to test their ability to increase healthspan by a range of different parameters including lifespan, reproduction and motility.

As part of the van Oosten-Hawle and Radford groups, you will receive multidisciplinary training at the interface between state-of-the-art genetics, whole-organism biology and biochemistry and structural biology.

More information on research in the van Oosten-Hawle laboratory and Radford laboratory can found at:
https://www.vanoostenhawlelab.com/
https://biologicalsciences.leeds.ac.uk/biological-sciences/staff/127/professor-sheena-radford


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 2020.

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

O'Brien et al., Cell Reports (2018) Jun 26;23(13):3905-3919;

Ladanza et al., Nature Comms (2018)9: 4517

Benseny-Cases, et al., J. Biol. Chem (2019)294: 9392

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