Explaining the elusive first step in neurodegenerative diseases by solving the structures of disordered proteins in physiological environments. MRC GW4 BioMed DTP PhD studentship for 2026/27 Entry, Department of Biosciences Ref: 5637

Supervisors

Lead Supervisor:  Dr Jonathan Phillips - University of Exeter - Department of Biosciences

Co-Supervisors

Professor Akshay Bhinge - University of Exeter - Department of Clinical and Biomedical Sciences 

The GW4 BioMed2 MRC DTP is offering up to 17 funded studentships across a range of biomedical disciplines, with a start date of October 2026.

These four-year studentships provide funding for fees and stipend at the rate set by the UK Research Councils, as well as other research training and support costs, and are available to UK and International students.

About the GW4 BioMed2 Doctoral Training Partnership

The partnership brings together the Universities of Bath, Bristol, Cardiff (lead) and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities, with opportunities to participate in interdisciplinary and 'team science'. The DTP already has over 90 studentships over 6 cohorts in its first phase, along with 80 students over 4 cohorts in its second phase.

The 122 projects available for application, are aligned to the following themes;

• Infection, Immunity, Antimicrobial Resistance and Repair

• Neuroscience and Mental Health

• Population Health Sciences

Applications open on 1 September 2025 and close at 5.00pm on 20th October 2025.

Please note that we may close the application process before the stated deadline if an unprecedented number of applications are received– check our website for details.

Studentships will be 4 years full time. Part time study may also be available.

Project Information

Research Theme:  Neuroscience & Mental Health

Summary:  

Neurodegenerative diseases, such as Parkinson’s disease, are strongly linked to the aggregation of intrinsically disordered proteins (IDPs). However, the precise triggers and mechanisms driving this process remain unclear without molecular structural detail. Determination of 3d protein structure has advanced recently (2024 Nobel Prize for AlphaFold) but only explains folded proteins. IDPs are a major frontier because they are exquisitely sensitive to environmental conditions, dramatically changing their molecular structure in response to stimuli and cellular trafficking.  Here, we will determine IDP structures in their native physiological environments to explain their influence on the formation of toxic aggregates and neuronal cell death. 

Description:

Opportunity: 

Alpha-synuclein in an intrinsically disordered protein (IDP) central to neurodegenerative diseases including Parkinson’s, dementia, and Multiple System Atrophy. Expressed in presynaptic terminals, alpha- synuclein mediates critical functions through conformational plasticity and forms neurotoxic Lewy bodies though largely unresolved mechanisms. Moreover, IDP conformational ensembles are highly dynamic and exquisitely sensitive to environmental conditions. This prevents conventional structural elucidation and thus hinders attempts to understand structure:function relationships underpinning their biological role. Hydrogen/deuterium-exchange mass spectrometry (HDX- MS) when measured with millisecond time resolution can overcome these limitations and enable the characterization of alpha-synuclein’s behaviour within biologically relevant contexts providing critical insight into its native structure-function relationship. 

This project will ultimately yield an experimentally grounded model of alpha-synuclein under biologically relevant conditions, enabling the development of a more realistic structure-function relationship to accelerate research into Synucleinopathies and deliver previously unattainable neurobiological insights. More broadly, these efforts will demonstrate a robust and insightful approach for structural elucidation of IDPs, and facilitate the development of a powerful condition-aware interpretive framework for HDX-MS. 

Background: 

The intrinsically disordered protein (IDP) alpha-synuclein is central to synucleinopathies, a class of neurodegenerative diseases including Parkinson’s, Lewy body dementia, and Multiple System Atrophy which affect a growing population globally. While alpha-synuclein has been extensively studied, its physiological functions and pathological behaviour remain challenging to meaningfully evaluate. Alpha-synuclein exists as an ensemble of structures that is functionally dependent on it cellular environment. Consequently, conventional structural biology methods and even AI-based tools like AlphaFold, offer little insight into its behaviour within a biologically relevant context. This lack of meaningful structural insights has stifled efforts to unravel the mechanisms driving aggregation and toxicity, identify biomarkers of disease progression, and ultimately develop suitable therapeutics against synucleinopathies (Zacharopoulou JACS 2025). 

Hydrogen-deuterium exchange mass spectrometry (HDX-MS) is a uniquely powerful tool for probing the structural dynamics of IDPs like alpha-synuclein. By measuring regional variations in the rate of backbone amide proton transfers in a deuterium rich buffer, HDX-MS can identify transient structural features. Critically, HDX-MS studies are amenable to physiologically relevant conditions including cellular mimics and lysates, making it ideal for capturing the conformational ensemble of alpha-synuclein under native condition (Seetaloo Anal. Chem. 2022). HDX-MS data can be leveraged using ensemble reweighting strategies wherein populations of structures generated by molecular dynamics (MD) simulations are adjusted to optimize agreement with experimental data and reveal the most probable conformations under specified conditions. Although widely utilized, the utility of this approach for modelling IDPs like alpha-synuclein within a biologically relevant context has traditionally been critically limited by data quality. This work seeks to leverage the globally unique 1 ms time-resolved approach developed in the Phillips lab to generate high-precision rigorously parameterized HDX- MS data, that can be integrated into existing ensemble reweighting pipelines, to generate atomistic models of alpha-synuclein that are both experimentally grounded and biologically relevant. This will directly support efforts to probe the structural basis of synucleinopathies, delivering previously unattainable neurological insights and laying the foundation for therapeutic targeting and meaningful biomarker discovery. 

Experimental Design / Aim: 

The student will use HDX-MS to probe alpha-synuclein’s conformational ensemble within compositionally distinct cellular mimics that replicate the complexities of its native environment. Then they will build towards endogenous protein measurements via addition of physiological extracts (blood plasma; neuronal extracts such as synaptosomes and lysosomes) complete with endogenous partners. This will build on the neuronal stem cell culture expertise of the Bhinge group, enabling the relevant cell line development of alpha-synuclein familial mutants, cell extracts and sample generation for orthogonal studies (e.g. cross-linking mass spectrometry). By incorporating well-established controls into the Phillips lab’s robust millisecond HDX-MS workflow, we will chemically parameterize solution conditions allowing for more rigorous condition- aware data comparisons and unambiguous evaluation of HDX behaviour within these complex environments. These data can then be used to constrain molecular dynamics driven ensemble reweighting to elucidate the protein’s native conformational ensemble under the precise physiological conditions studied. By replicating this approach across familial mutants of alpha-synuclein (e.g. A53E; A30P), we hope to explain previously unresolved structural determinants of Parkinson’s pathophysiology.

Skills and Training: 

The prospective student will work closely with a cross-departmental interdisciplinary supervisory team at the Living Systems Institute, University of Exeter: Dr Jonathan Phillips (Biosciences) and Dr Akshay Bhinge (Clinical and Biomedical Sciences). This project will provide opportunities for the student to develop well-rounded skills: including stem cell biology techniques, biochemistry, high resolution mass spectrometry, microfluidics, statistical data analysis, computational modelling and strong written and oral communication. Once trained in the fundamental aspects for sample generation and mass spectrometry analysis, the student will be highly autonomous and responsible for driving the project and expected to present and pro-actively discuss their findings with the team and externally at scientific meetings. Each supervisory team member will provide the student with access to complementary expertise important for guiding the student’s project and career progression.

Funding

This studentship is funded through GW4BioMed2 MRC Doctoral Training Partnership. It consists of UK tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£20,780 p.a. for 2025/26, updated each year).

Additional research training and support funding of up to £5,000 per annum is also available.

Eligibility

Residency:

The GW4 BioMed2 MRC DTP studentships are available to UK and International applicants. Following Brexit, the UKRI now classifies EU students as international unless they have rights under the EU Settlement Scheme. The GW4 partners have agreed to cover the difference in costs between home and international tuition fees. This means that international candidates will not be expected to cover this cost and will be fully funded but need to be aware that they will be required to cover the cost of their student visa, healthcare surcharge and other costs of moving to the UK to do a PhD.  All studentships will be competitively awarded and there is a limit to the number of International students that we can accept into our programme (up to 30% cap across our partners per annum).

Academic criteria:

Applicants for a studentship must have obtained, or be about to obtain, a first or upper second-class UK honours degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences.  Applicants with a lower second class will only be considered if they also have a Master’s degree. Please check the entry requirements of the home institution for each project of interest before completing an application. Academic qualifications are considered alongside significant relevant non-academic experience.

English requirements:

If English is not your first language you will need to meet the English language requirements for the University of Exeter by the start of the programme. Please refer to the details in the following web page for further information https://www.exeter.ac.uk/study/englishlanguagerequirements/

Please check the relevant English Language requirements of the university that will host the PhD project.  

Data Protection

If you are applying for a place on a collaborative programme of doctoral training provided by Cardiff University and other universities, research organisations and/or partners please be aware that your personal data will be used and disclosed for the purposes set out below.

Your personal data will always be processed in accordance with the General Data Protection Regulations of 2018. Cardiff University (“University”) will remain a data controller for the personal data it holds, and other universities, research organisations and/or partners (“HEIs”) may also become data controllers for the relevant personal data they receive as a result of their participation in the collaborative programme of doctoral training (“Programme”).

Further Information

For an overview of the MRC GW4 BioMed programme please see the website www.gw4biomed.ac.uk

Entry requirements

Academic Requirements

Applicants for a studentship must have obtained, or be about to obtain, a first or upper second-class UK honours degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences. Applicants with a lower second class will only be considered if they also have a Master’s degree. Please check the entry requirements of the home institution for each project of interest before completing an application. Academic qualifications are considered alongside significant relevant non-academic experience.

English Language Requirements

If English is not your first language you will need to meet the English language requirements for the University of Exeter by the start of the programme. Please refer to the relevant university website for further information.  This will be at least 6.5 in IELTS or an acceptable equivalent.  Please refer to the English Language requirements web page for further information.

Please check the relevant English Language requirements of the university that will host the PhD project. 

How to apply

A list of all the projects and how to apply is available on the DTP’s website at gw4biomed.ac.uk.  You may apply for up to 2 projects and submit one application per candidate only.

Please complete an application to the GW4 BioMed2 MRC DTP for an ‘offer of funding’.  If successful, you will also need to make an application for an 'offer to study' to your chosen institution.

Please complete the online application form linked from our website by 5.00pm on Monday, 20th October 2025.  Please note that we may close the application process before the stated deadline if an unprecedented number of applications are received– check the DTP’s website for details and updates

If you are shortlisted for interview, you will be notified from Tuesday, 23rd December 2025.  Interviews will be held virtually on 27th and 28th January 2026.  

Further Information

For informal enquiries, please contact GW4BioMed@cardiff.ac.uk

For project related queries, please contact the respective supervisors listed on the project descriptions on our website.

Summary