GW4 BioMed3 MRC DLP PhD project: Decoding Neurodevelopmental Disorders: From Patient Variants to Disease Mechanisms

About the project

About the Project This project is one of several in competition for funding from the GW4 BioMed3 MRC Doctoral Landscape Programme (DLP), which is offering up to 17 studentships for entry in September 2027. The partnership brings together the Universities of Bath, Bristol, Cardiff 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. More information may be found on the DLP’s website . Please note that the application process may close early to either home or international candidates (or both) before the stated deadline if an unprecedented number of applications are received – check the DLP’s website for details and updates. Supervisory Team: Dr Julien Licchesi (University of Bath) Dr Greg Ngo (University of Cardiff) Prof Christiane Berger-Schaffitzel (University of Bristol) Dr Nikolas Nikolaou (University of Exeter) Background: Neurodevelopmental disorders (NDDs), including autism spectrum disorder, intellectual disability and developmental delay, affect millions of children worldwide. Although genomic sequencing has identified many disease-associated variants, the mechanisms linking genetic variation to altered brain development remain poorly understood. HECTD1 is an E3 ubiquitin ligase required for embryonic and postnatal brain development. E3 ligases regulate proteostasis by controlling the stability and function of cellular proteins, thereby coordinating signalling pathways essential for normal development. Variants in HECTD1 have been identified in individuals with autism spectrum disorder and severe developmental conditions, but the clinical significance and functional consequences of most variants remain unknown. Computational analyses predict that some variants destabilise HECTD1, while others may impair ligase activity, substrate recognition or downstream signalling. However, experimental evidence is lacking. Understanding how HECTD1 variants affect protein function and neurodevelopment will provide insight into disease mechanisms and establish approaches for studying other NDD-associated genes within the ubiquitin system. Research Question Determine whether and how HECTD1 variants alter cellular signalling networks during neurodevelopment. Objective 1: Define how HECTD1 variants alter protein structure and function The student will investigate how disease-associated HECTD1 variants affect protein stability, structure and ubiquitin ligase activity. Computational modelling will be integrated with structural, biochemical and cell-based studies to determine whether variants act through protein destabilisation, altered conformational dynamics or impaired catalytic function. Variant stability and localisation will be assessed using microscopy, flow cytometry and immunoblotting approaches. Objective 2: Investigate variant-specific mechanisms in human stem cell models CRISPR-Cas9 genome editing will generate isogenic induced pluripotent stem cell (iPSC) lines carrying selected patient-derived HECTD1 variants. Emphasis will be placed on variants that retain protein stability, as these may reveal pathogenic mechanisms involving altered substrate recognition or signalling outputs. The project will benefit from established expertise in modelling neurodevelopmental disorder-associated variants in human stem cells. Objective 3: Identify HECTD1 substrates and proteostasis pathways in neural progenitor cells The molecular targets of HECTD1 remain poorly defined, particularly in neural cell types relevant to NDDs. Human neural progenitor cells (NPCs) provide an ideal model because HECTD1 plays critical roles during early neurodevelopment. Using quantitative proteomics and interactome mapping the student will identify HECTD1-interacting proteins and potential substrates in wild-type and variant NPCs. These studies will define the signalling and proteostasis networks regulated by HECTD1 and determine how disease-associated variants perturb them. Objective 4: Determine how early molecular defects influence neuronal network function To establish how developmental molecular defects translate into neuronal dysfunction, selected HECTD1 iPSC lines will be differentiated into glutamatergic neurons. Neuronal maturation, excitability and network activity will be assessed using multielectrode array (MEA) technology. These studies will determine whether HECTD1 variants alter neuronal connectivity and synchronisation, thereby linking disrupted protein quality-control pathways with clinically relevant neurophysiological phenotypes. Objective 5: Validate disease mechanisms in zebrafish HECTD1 knock-in models Selected patient-derived HECTD1 variants will be introduced into zebrafish using genome-editing approaches. Zebrafish provide a powerful model for assessing neural tube development, brain formation and behaviour. These experiments will test molecular pathways identified through cellular and proteomic studies and establish mechanistic links between genetic variation, disrupted developmental signalling and neurodevelopmental outcomes. Student Ownership and Opportunities to Steer the Project This multidisciplinary project integrates structural biology, proteomics, stem cell biology, electrophysiology and animal models. The student will play a central role in prioritising work packages, selecting variants for detailed analysis and refining research directions as findings emerge. Flexibility will allow pursuit of the most promising mechanistic hypotheses while ensuring delivery within the PhD timeframe. The project will also evolve as new HECTD1 variants are identified, providing opportunities for engagement with clinical researchers, patient communities and the broader neurodevelopmental disorders field. Requirements: Applicants must have obtained, or be about to obtain, a first or upper second-class UK honours degree (or international equivalent) in an appropriate area including Biochemistry, Biomedical Sciences, Neurosciences. Applicants with a lower second-class degree will only be considered if they have a grade of Merit or above in a master’s degree. Academic qualifications are considered alongside significant relevant non-academic experience. Non-UK applicants will also be required to have met the English language entry requirements of the University of Bath. Enquiries and Applications: Informal enquiries are welcomed and should be directed to Dr Licchesi: Jdfl20@bath.ac.uk Formal applications must be submitted direct to the GW4 BioMed3 DLP using their online application form . A list of all the projects and details on how to apply are available DLP’s website . You may apply for up to 2 projects and submit one application per candidate only. APPLICATIONS CLOSE AT 17:00 (GMT) ON 21 OCTOBER 2026. IMPORTANT: You do NOT need to submit an application to the University of Bath at this stage. Equality, Diversity and Inclusion: We value a diverse research environment and aim to be an inclusive university, where difference is celebrated and respected. We welcome and encourage applications from under-represented groups. If you have circumstances that you feel we should be aware of that have affected your educational attainment, then please feel free to tell us about it in your application form. The best way to do this is a short paragraph at the end of your personal statement.

Research areas