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(BBSRC NWD) A novel redox mechanosignalling nexus in the synapse that is misregulated in neurodegeneration

Funding
Funded
Study mode
Full-time
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Subject area
Biological and Biomedical Sciences
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Overview

During the early stages of neurodegeneration, alterations in extracellular matrix (ECM) stiffness and increases in oxidative stress occur. Neurons have advanced signalling mechanisms that sense and respond to these changes to maintain homeostasis. However, over time these physiological insults result in loss of homeostasis leading to damage in the information transmitting synapses and loss of memory.

About this opportunity

Fluctuations in the balance of reducing and oxidising conditions in cells is referred to as “Redox” and this project will explore how redox signalling and mechanical signalling are coupled. The project is based on exciting new preliminary data and will look at a newly identified, direct link between the cell’s mechanosensitive machinery and its redox signalling systems that converges on the protein talin.

We predict that understanding the convergence of these signal pathways will enhance our understanding of healthy brain aging. Furthermore, as oxidative stress is known to have a central role in neurodegeneration, we hope to identify novel therapeutic strategies.

Background

Much of cell signalling occurs at the attachment points cells make with the surrounding ECM. In the brain these connections between neurons and are mediated via the integrin family of ECM receptors that are coupled to the cell’s cytoskeleton via the synaptic scaffolds protein, talin. For years talin was thought to be a simple scaffold protein but we discovered that talin is actually an exquisite mechanosensor with 13 force-dependent binary switch domains that control signalling outputs. These binary switches coordinate multiple synaptic enzymes including CDKL5, PKA and Src, positioning talin as a central mechanical signalling scaffold in the synapse. More recently, we discovered that Amyloid Precursor Protein (APP) binds to talin directly linking mechanotransduction to neurodegeneration and Alzheimer’s Disease.

The use of fluorescent probes that report on hydrogen peroxide/oxidative stress have revealed that the leading edge of migrating cells sees bursts of increased oxidation, and that the cells use these changes to direct their behaviour.

Hypotheses

This project will test three hypotheses; 1) integration of mechanosensing and redox sensing at adhesion sites represents an unexplored signalling nexus. 2) misregulated oxidative stress perturbs this signalling nexus and drives neurodegeneration. 3) understanding this nexus will identify novel therapeutic strategies for targeting neurodegenerative disease.The project will combine biochemistry and biophysics to understand how redox changes impact talin function with cell biology approaches using fluorescent reporters to study localised redox changes on talin signalling. We will develop chemical genetic tools to locally manipulate redox at adhesion sites. Once optimised in U2-OS cancer cells these methodologies will be applied in neuronal cells, to identify how redox spikes alter the mechanical computation machinery in synapses. Finally, we will use proteomic approaches to explore how altering redox conditions changes these signalling complexes.

Further reading

1. Kang M, Otani Y, Guo Y, Yan J, Goult BT* and Howe A*. (2024) The focal adhesion protein talin is a mechanically-gated A-kinase anchoring protein (AKAP). PNAS 121(13):e2314947121 PMID: 38513099
2. Gough RE, Jones MC, Zacharchenko T, Le S, Yu M, Jacquemet G, Muench SP, Yan J., Humphries JD, Jørgensen C, Humphries MJ and Goult BT*. (2021) Talin mechanosensitivity is modulated by a direct interaction with cyclin dependent kinase-1. J Biol Chem 297(1):100837 PMID: 34118235
3. Otani Y, Goodall E, Srinivasan V, Ball NJ, Barnett SFH, Zech T, Saarikangas J and Goult BT. (2025) Cyclin-dependent kinase-like 5 (CDKL5) binds to talin and is anchored at the postsynaptic density via direct interaction with PDZ domains. bioRxiv
4. Kritsiligkou P, Bosch K, Shen TK, Meurer M, Knop M, Dick TP. (2023) Proteome-wide tagging with an H2O2 biosensor reveals highly localized and dynamic redox microenvironments. PNAS 120:48: e2314043120
5. Byron A, et al. (2022) Characterisation of a nucleo-adhesome. Nature Comms 13:1:3054

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Who is this for?

Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.

International applicants

We are only able to offer a limited number of full studentships to applicants outside the UK. Therefore, full studentships will only be awarded to exceptional quality international candidates due to the competitive nature of this scheme.

International applicants must ensure they meet the academic eligibility criteria (including English language) before applying. Visit our English Language requirements page to find out more.

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Liverpool, and is at the heart of all of our activities. The full equality, diversity and inclusion statement can be found on our website.

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How to apply

  1. 1. Contact supervisors

    The student will be embedded in the Biochemistry, Cell and Systems Biology department at University of Liverpool and be part of the Liverpool Interdisciplinary Neuroscience Centre. The supervisory team are experts in structural mechanobiology of talin (Goult Lab), redox biology (Kritsiligkou Lab) and proteomics, cell biology and neuronal cell culture (Byron Lab, Manchester).

    https://www.liverpool.ac.uk/people/ben-goult

    https://www.liverpool.ac.uk/people/paraskevi-kritsiligkou

    https://research.manchester.ac.uk/en/persons/adam.byron

  2. 2. Prepare your application documents

    Browse our BBSRC NWD in Bioscience projects and discover one you’re passionate about that matches your interests, ambitions and goals.

    Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

    How to Apply

    All applications should be submitted through the University of Manchester application portal.

    Apply directly via this link, and select BBSRC DTP PhD as the programme of study. You may apply for up to two projects from the programme via this scheme. To do so, submit a single online application listing both project titles and the names of both main supervisors in the relevant sections.

    Please ensure that your application includes all required supporting documents:

    • Curriculum Vitae (CV)
    • Supporting Statement
    • Academic Certificates and Transcripts

    Incomplete or late applications will not be considered.

    Applications should not be made through the University of Liverpool’s application portal.

    You must submit your application form along with the required supporting documents by the deadline date. You can select up to two projects on one single application, noting the title of each project from the advert and the supervisor name. This can include two projects from one institution or a project from each institution.

    Once you have completed your application, you’ll receive a confirmation email.

    Deadline: Sunday 7th December, midnight (UK time)

    Late or incomplete applications will not be considered.

    If you need help with this stage of the process, or have any queries regarding your eligibility (such as if you achieved unexpectedly low degree results due to extenuating circumstances), please contact the Liverpool BBSRC team for advice at 

  3. 3. Apply

    Finally, register and apply online. You'll receive an email acknowledgment once you've submitted your application. We'll be in touch with further details about what happens next.

    Once you have applied through the University of Manchester portal, and if you are successfully offered a studentship following a formal interview, you will be instructed to apply formally through the University of Liverpool. You must only do this once you have been instructed to do so.

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Funding your PhD

These studentships are available to UK and international applicants, and provide funding for tuition fees and stipend at the UKRI rate, subject to eligibility, for four years. This does not include any costs associated with relocation. This scheme is open to both UK and international applicants.

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Contact us

Have a question about this research opportunity or studying a PhD with us? Please get in touch with us, using the contact details below, and we’ll be happy to assist you.

Liverpool BBSRC team
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