Characterisation of TDP-43 mediated JNK signaling in neurodegenerative diseases ALS and FTD

About the Project

Lead supervisor:Dr Han-Jou Chen

Co-supervisors:Dr G Evans and Prof Sean Sweeney

The student will be registered with the Department of Biology

RNA-binding protein TDP-43 is an important protein closely associated with many neurodegenerative diseases, ranging from motor neurone disease (e.g. Amyotrophic Lateral Sclerosis, ALS) to dementia such as Frontotemporal Dementia (FTD). Neurodegenerative diseases are commonly characterised by aberrant protein aggregate pathology which is believed to be the key driving force of the gradual neuronal loss. As the main pathological proteins associated with 97% of ALS and 45% of FTD, the aggregation and functional disruption of TDP-43 is therefore the keen research focus of the field to unlock the mechanism triggering and promoting ALS and FTD. The overarching aim of our research is to dissect the molecular pathogenesis underlying the development and progression of neurodegeneration, identifying new therapeutic targets to promote the development of novel treatments for the diseases.

In our earlier study using transcriptomic, cellular and in vivo approaches, it was identified that the ALS/FTD-linked RNA-binding deficient TDP-43 causes a distinct delayed toxicity and JNK signaling-mediated compensatory response (Magarotto et al., 2025 HMG). While JNK activation has been linked to apoptosis observed in disease late stage, this is the first time it is implicated in a potential early degeneration event. This research will further dissect the interplay between JNK signaling and TDP-43, with particular focuses on answering: 1) how disrupted TDP-43 triggers JNK signaling, and 2) how aberrant JNK signaling contributes to neurodegeneration. Using a wide range of molecular and cell biology approaches, this project will interrogate the transcriptomic data and validate the findings in established cell and animal models of ALS. The models used in this study include in vitro systems, established cell lines, rodent primary neurones and transgenic Drosophila, with the potential of validating key results in human iPS-derived neurones, transgenic mouse tissue and patient post-mortem tissues. The interaction between TDP-43 and various JNK signaling components will be investigated using in vitro assay and sophisticated cell-based analysis. This project will also generate new cell and transgenic models to investigate the impact of the TDP-43-JNK interaction on neuronal function and in vivo physiology. Advanced microscopy and imaging analysis will be used to provide detailed characterisation of neuronal morphology and functionality. Overall, we wish to invite talented students with a keen interest in molecular/cell biology and in studying and finding a cure for neurodegenerative diseases to join our research. With increasing number of people affected by neurodegenerative diseases, the research will be vital to relieve the burden of the diseases for a sustainable future.

The University of York is committed to recruiting future scientists regardless of age, ethnicity, gender, gender identity, disability, sexual orientation or career pathway to date. We understand that commitment and excellence can be shown in many ways and we have built our recruitment process to reflect this. We welcome applicants from all backgrounds, particularly those underrepresented in science, who have curiosity, creativity and a drive to learn new skills.

The Department of Biology holds an Athena SWAN Gold Award. We are committed to supporting equality and diversity and strive to provide a positive working environment for all staff and students.

Entry Requirements: Students with, or expecting to gain, at least an upper second class honours degree, or equivalent, are invited to apply. The interdisciplinary nature of this programme means that we welcome applications from students with any biological, chemical, and/or physical science backgrounds.

Programme: PhD in Biomedical Science (3 year)

Start Date: 21 September 2026