Fixed-term

Funding – self-funded/externally sponsored applicants  (PhD Fees can be found here) Applications are accepted year round Standard Entry dates – January and September Applicants are expected to have a degree (equivalent of Honours or Masters) in a relevant discipline. Neural cell adhesion molecule (NCAM) belongs to the immunoglobulin superfamily of cell adhesion molecules. They are expressed in the brain and associated with adhesions between neurons and glial cells. NCAM carries a specific post-translational modification that adds polysialic acid (PSA) to the extracellular compartment of the NCAM molecule. PSA is a long, linear alpha2,8-linked carbohydrate molecule. The amount of PSA-NCAM on the cell surface is regulated by both the addition of PSA onto NCAM, and through an endocytosis-driven internalisation and rapid degradation of the polysialic acid. The addition is conducted by enzymes ST8SiaII (STX) and ST8SiaIV (PST), two Ca2+-dependent Golgi-complex-associated polysialyltransferases. This results in the presence of large negatively charged hydrophilic molecules on the cell surface, which causes steric impediments with receptors and the extracellular matrix (ECM) molecules, diminishing cell-adhesion and ECM interactions. PSA-NCAM is most prominently expressed in the developing nervous system where it promotes the migration of neural and non-neural precursors, as well as facilitating axonal pathfinding and synaptogenesis. With regards to adult brain function, PSA-NCAM is involved in brain tumour invasion and migration and also in Alzheimer’s disease there are deficiencies in PSA-NCAM in areas of high plasticity and early affected brain regions. The proposed study will look for PSA-NCAM modulators by testing PSA-NCAM levels by phenotypically screening the impact of a wide range of compounds in the search for modulators. Our hypothesis is that modulation of PSA-NCAM may hold therapeutic value either for brain tumours or neurodegenerative diseases. Specific questions: What classes of compounds up or down regulate PSA-NCAM levels? What is the activity of these compounds – do they change the polysialylation rate, or do they alter the desialylation rate? What are the targets of PSA-NCAM-modulating compounds? How can in silicon modelling be used to create analogues of PSA-NCAM modifiers The skills a student would develop are: Cell culture, high throughput drug screening, cytology, high throughput imaging, in silico modelling, synthetic/medicinal chemistry. How to apply Please contact the principal project supervisor to discuss your interest further, see supervisor details below. For general enquiries, contact SLS-PhDAdmin@dundee.ac.uk Supervisors Principal supervisor Person Professor Mahmood Ahmed Professor, Head of Medicinal Chemistry mahmed002@dundee.ac.uk +44 (0)1382 383062

Funding – self-funded/externally sponsored applicants   (PhD Fees can be found here) Applications are accepted year round Standard Entry dates – January and September Applicants are expected to have a degree (equivalent of Honours or Masters) in a relevant discipline. The challenge Mutations in the kinase LRRK2 are one of the most common inherited causes of Parkinson’s disease, yet we still don’t fully understand how LRRK2 drives disease at the molecular level (1, 2). Our lab aims to change that, by uncovering how LRRK2 signalling is regulated, how it malfunctions in Parkinson’s disease, and how these insights can guide the discovery of new biomarkers and therapeutic targets. The discovery We have identified a previously unknown signalling pathway triggered by endolysosomal stress, a hallmark of many Parkinson’s disease models (3, 4). Mutations in LRRK2 and VPS35 cause cargo misrouting and abnormal recruitment of LRRK2 to stressed lysosomes, where it hyperphosphorylates a subset of Rab GTPases. These phosphorylated Rabs bind the effector RILPL1, which then interacts directly with the lysosomal membrane protein TMEM55B via a conserved TMEM55B Binding Motif (4). We have recently solved the crystal structure of the TMEM55B–RILPL1 interactor complex, revealing the molecular details of this interaction for the first time. To probe its functional importance, we have developed two unique knock-in mouse models: A TMEM55B mutant unable to bind RILPL1 A RILPL1 mutant unable to bind TMEM55B The project You will investigate how disrupting the TMEM55B–RILPL1 axis impacts lysosomal biology and Parkinson’s disease -relevant signalling. Using brain tissue and primary cells from these mouse models, you will perform lysosome immunoprecipitations (Lyso-IPs) followed by deep proteomic, lipidomic, and phosphoproteomic profiling using advanced mass spectrometry. You will analyse multi-omics datasets to map signalling changes, identify key effectors, and validate them through mechanistic cell biology experiments. What you will gain Hands-on training in cutting-edge mass spectrometry (proteomics, lipidomics, phosphoproteomics) Expertise in primary cell isolation and culture from mouse models Advanced techniques in lysosome biology, including LysoTag-IP Multi-omics data analysis and interpretation skills Experience designing and executing mechanistic follow-up experiments Opportunities to collaborate with world-leading researchers, clinicians, and pharmaceutical partners Engagement with people living with Parkinson’s disease to connect your research to patient impact Why this matters This is a unique chance to help unravel a completely new branch of the LRRK2 signalling network, one that could reshape our understanding of Parkinson’s disease and reveal entirely new therapeutic avenues. You’ll join a highly collaborative, internationally recognised research environment at the University of Dundee’s MRC-PPU, known for its pioneering work in protein phosphorylation and ubiquitylation biology. If you’re passionate about discovery science with clear disease relevance and want to master an advanced, interdisciplinary skill set that’s in demand in both academia and industry this project offers a rare and exciting opportunity. How to apply Please contact the principal project supervisor to discuss your interest further, see supervisor details below. For general enquiries, contact SLS-PhDAdmin@dundee.ac.uk Supervisors Principal supervisor Person Professor Dario Alessi Science Director, Professor of Signal Transduction d.r.alessi@dundee.ac.uk +44 (0)1382 388058

Funding – self-funded/externally sponsored applicants   (PhD Fees can be found here) Applications are accepted year round Standard Entry dates – January and September Applicants are expected to have a degree (equivalent of Honours or Masters) in a relevant discipline. Parkinson’s Disease or PD is the second fastest growing neurodegenerative disease in the UK. PD is an age-associated disease characterized by tremors, change in gait, loss of appetite and loss or reduction in the sense of smell (anosmia). Anosmia is reported in individuals with PD years to decade before motor symptoms (tremors and loss of dopaminergic neurons). Anosmia has a huge impact on the quality-of-life impacting body weight, mood and safety. Mutations in leucine rich repeat kinase lrrk2 gene or in glucocerebrosidase gene gba1 are most common in PD and both sets of people report anosmia. Congenital anosmia is associated with loss of a sensory structure, primary cilium, in the sensory neurons in the nose. Cilia loss is also seen in some of the neurons in the striatum (part of human brain linked to motor control) indicating cilia loss as a major feature of PD pathology. A recent survey from Parkinson’s UK indicated that people with PD support research on anosmia so that treatments for motor and non-motor symptoms of PD could be found. This PhD project is centered on obtaining mechanistic insights into anosmia and neuronal cilia loss using a genetically tractable nematode Caenorhabditis elegans. The PhD student will express mutant copy of human lrrk2 gene in C. elegans (LRRK2 PD model) and mutate neuronal glucocerebrosidase gba-4 (GBA PD model) by CRISPR/CAS9 to study effects on cilia morphology, odorant structure expression and receptor function in both models using robust assays established in the Singh laboratory. The student will also study the impact of age on cilia morphology and on neuronal gene expression to compare the two models of genetic PD. The outcome of the study will uncover mechanistic basis of cilia loss in PD and pave the way for treatment not only for anosmia but also for restoring motor symptoms. The student will acquire training in C. elegans maintenance, genome editing and transgenesis, imaging of olfactory neurons, transmission electron microscopy for cilia, chemotaxis assays, and transcript analysis by qRT-PCR. The student will be provided training in scientific writing, statistics and data management. The student will also receive mentoring support in an inclusive environment. How to apply Please contact the principal project supervisor to discuss your interest further, see supervisor details below. For general enquiries, contact SLS-PhDAdmin@dundee.ac.uk Supervisors Principal supervisor Person Dr Varsha Singh Senior Lecturer and Royal Society Wolfson Fellow vsingh001@dundee.ac.uk +44 (0)1382 388898

Funding – self-funded/externally sponsored applicants   (PhD Fees can be found here) Applications are accepted year round Standard Entry dates – January and September Applicants are expected to have a degree (equivalent of Honours or Masters) in a relevant discipline. Meiosis research is of paramount importance for several aspects of human life including fertility, genetic diseases, and crop improvement. Insights into the intricate mechanisms governing the different meiotic stages has come from several organism like yeast, flies, nematodes, plants, and mammals. This diversity has allowed to uncover common and specific mechanisms in place to guarantee the faithful and timely generation of euploid gametes. During meiosis, a single round of DNA replication is followed by two consecutive rounds of chromosome segregation (meiosis I and II) to generate haploid gametes. While homologous chromosomes dissociate in meiosis I, sister chromatid cohesion (SCC) must be maintained until segregation at meiosis II. Protein phosphatases play a key role in the protection of SCC during meiosis I. In the nematode C. elegans, Protein Phosphatase 1 (PP1) is the phosphatase involved in SCC protection. Additionally, PP1 regulates meiotic chromosome segregation, and therefore PP1 is essential for the generation of normal (euploid) gametes. Despite its key roles, how PP1 function is regulated during meiosis is very poorly understood. Therefore, our goal in the current project is to understand the molecular mechanisms involved in PP1 regulation during meiotic chromosome segregation. We will focus on understanding 1) the role of the ATPase p97 in regulating PP1 during meiosis; 2) the mechanism of PP1 kinetochore recruitment; and 3) how/why PP1 dysregulation leads to failed meiotic chromosome segregation. We will use a combination of high-resolution time-lapse microscopy together with biochemical approaches and genome editing to reach our goal and in doing so we will achieve a better understanding of the regulation of key events during oocyte meiosis. The present project has three clearly defined objectives which, together, will achieve the overall aim of understanding the molecular mechanisms involved in PP1 regulation during meiotic chromosome segregation. AIM 1. What are the CDC-48 co-factors involved in PP1 regulation? In this aim, the objective is to identify and characterise the adaptors involved in targeting CDC-48 to perform its meiotic function. AIM 2. How is PP1 recruited to prometaphase I meiotic chromosomes? How PP1 is targeted to kinetochore/chromosome during Prometaphase I is not known and does not involve the widely studied kinetochore protein and PP1 interactor, KNL-1. To achieve this, we first need to identify meiosis-specific PP1 interactors. AIM 3. Understanding how PP1 dysregulation leads to failed meiosis The last aim will provide an understanding of what are the vital events regulated by PP1 during meiosis. By characterising the molecular mechanisms involved in PP1 regulation during meiotic chromosome segregation, we will achieve a better understanding of the regulation of key events during oocyte meiosis. Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research.  We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education. How to apply Please contact the principal project supervisor to discuss your interest further, see supervisor details below. For general enquiries, contact SLS-PhDAdmin@dundee.ac.uk Supervisors Principal supervisor Person Dr Fede Pelisch Principal Investigator/Senior Lecturer f.pelisch@dundee.ac.uk +44 (0)1382 388600 Second supervisor Person Professor Karim Labib Professor k.p.m.labib@dundee.ac.uk

Funding – self-funded/externally sponsored applicants   (PhD Fees can be found here) Applications are accepted year round Standard Entry dates – January and September Applicants are expected to have a degree (equivalent of Honours or Masters) in a relevant discipline. Parasitic helminths (worms) can modulate the host immune response, to prevent the immune system from ejecting them. Our previous work has identified several families of proteins from an intestinal nematode: these proteins bind with high affinity to proteins of the immune system, either blocking the activity of the immune system, or changing the response induced. There are multiple effects of parasites on the immune system which have never been fully characterised. In this project we propose a new technique to screen for novel parasite-host interactions. We will first collect the secretions of the murine intestinal nematode Heligmosomoides polygyrus bakeri. These secretions (termed “HES”) contain several known immunomodulatory proteins, including HpARI (binds IL-33 (Osbourn, 2017, Immunity)), HpBARI (binds ST2 (Vacca, 2020, eLife)) and HpTGM (binds TGFBR2 (Johnston, 2017, Nat Commun)). We propose that by taking the total secretions of the parasite and mixing these with host cell homogenates, we can identify known and novel immunomodulatory binders. Through the use of gel filtration fractionation and mass spectrometry, we can estimate the molecular weight of each protein or complex in a mixture: if a parasite and host protein complex together they would increase in size on a gel filtration column. We will therefore begin by showing we can detect these size changes by mixing known immunomodulatory proteins with their known targets: HpARI with IL-33, HpBARI with ST2 and HpTGM with TGFBR2. We will then move onto using more complex mixtures of host cell lysates. If successful, this technique would allow us to use the secretions of less well understood parasites (e.g. human hookworms) to identify how these interact with their hosts. This project would therefore use protein characterisation (gel filtration, western blot, ELISA), and proteomic techniques (mass spectrometry), as well as bioinformatic analysis of large proteomic datasets to identify new parasite-host interactions. These parasite immunomodulatory proteins could have multiple future uses: they may make good vaccine candidates against parasitic infections, or the immunomodulatory proteins could be used as treatments for immune-mediated diseases. Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research.  We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education. How to apply Please contact the principal project supervisor to discuss your interest further, see supervisor details below. For general enquiries, contact SLS-PhDAdmin@dundee.ac.uk Supervisors Principal supervisor Person Dr Henry McSorley Reader hmcsorley001@dundee.ac.uk Second supervisor Person Professor Simon Arthur Professor j.s.c.arthur@dundee.ac.uk +44 (0)1382 384003

Funding – self-funded/externally sponsored applicants   (PhD Fees can be found here) Applications are accepted year round Standard Entry dates – January and September Applicants are expected to have a degree (equivalent of Honours or Masters) in a relevant discipline Amyotrophic lateral sclerosis (ALS)—the commonest type of motor neuron disease (MND)—is a rapidly progressive paralysing illness of mid-adulthood.  It has a lifetime risk of ~1 in 400, resulting from the selective neurodegeneration of upper and lower motor neurons (MNs).  ~10% of ALS is inherited, and the rest occurs spontaneously.  The median survival from symptom onset is 3 years and there are no significant treatments, and no cure.  The only globally licensed medication, Riluzole, prolongs survival by a few months on average, and was introduced in the mid 1990s.  Consequently, there is a major impetus to unravel the key molecular pathomechanisms to make a breakthrough. To date, mutations in >40 genes have been identified as a cause of familial ALS/MND that have significantly advanced our understanding of the pathogenesis.  Several encode or could interact with protein kinases, implicating dysregulation of protein phosphorylation in ALS pathogenesis, although a single coherent signalling pathway that explains MN degeneration remains elusive. Our lab studies two ALS mutations – C9ORF72 (which also causes fronto-temporal dementia) and NEK1 – using state-of-the-art human induced pluripotent stem cell models combined with CRISPR/Cas9 genome editing to generate motor neurons and also microglia.  We are also planning to develop organoid models.  We are particularly interested in dissecting out the proximal cellular signalling pathways involved in pathogenesis and we use quantitative ultrasensitive proteomics and phosphoproteomics (including of key neuronal compartments, such as the axon) to help address this, with mechanistic studies performed initially in cell lines.  We are also interested in identifying drivers of clinical heterogeneity, noting that 10-20% of people with ALS/MND live longer than 10 years.  We thus plan to comprehensively study motor neurons derived from people with sporadic ALS of different disease durations to identify key cellular and molecular signatures of aggressive versus less progressive disease to identify mediators of relative vulnerability and/or resilience. The successful applicant would be trained in human stem cell culture and neuronal/glial differentiation and genome editing.  A suite of molecular/biochemical techniques including mass spectrometry would be deployed under specialist training in the fantastic environment of the MRC Protein Phosphorylation & Ubiquitylation Unit.  There would be opportunities for public and patient engagement and involvement and potential collaboration with external MND sites within the UK and beyond. Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research.  We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education. How to apply Please contact the principal project supervisor to discuss your interest further, see supervisor details below. For general enquiries, contact SLS-PhDAdmin@dundee.ac.uk Supervisors Principal supervisor Person Dr Arpan Mehta Clinical Senior Lecturer / Honorary Consultant amehta001@dundee.ac.uk Second supervisor Person Professor Miratul Muqit Professor M.Muqit@dundee.ac.uk +44 (0)1382 388377