"PhD Studentship - Investigating the role of DNA Methylation in C9ORF72 Amyotrophic Lateral Sclerosis"

PhD Studentship - Investigating the role of DNA Methylation in C9ORF72 Amyotrophic Lateral Sclerosis

University of Exeter - HLS

Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disorder characterised by the selective loss of motor neurons in the brain and spinal cord. This leads to muscle weakness, paralysis, and premature death. Although substantial progress has been made in identifying the genetic causes of ALS, the mechanisms that determine motor neuron vulnerability and disease progression remain poorly understood, limiting the development of effective therapies.

Approximately 10–15% of ALS cases are familial, with the most common genetic cause being an abnormal expansion of a repeated DNA sequence within the C9ORF72 gene. In a subset of individuals with this genetic form of ALS, the expanded region undergoes DNA methylation, an epigenetic modification that can influence gene expression. Notably, several studies suggest that higher levels of methylation at the C9ORF72 locus are associated with slower disease progression and increased survival. However, the molecular basis of this apparent protective effect is currently unknown.

This fully funded PhD studentship aims to investigate how repeat length and DNA methylation within the C9ORF72 gene interact to influence motor neuron survival in ALS. The overarching objective of the project is to identify epigenetic mechanisms that modify disease severity and may represent targets for future therapeutic intervention.

The project will adopt an integrated experimental approach combining the analysis of post-mortem human brain tissue with patient-derived induced pluripotent stem cell (iPSC) models. Studies of donated brain tissue from individuals with C9ORF72-associated ALS will be used to characterise repeat length and methylation patterns across distinct neural cell types, providing insight into cell-type-specific disease mechanisms in the human nervous system.

In parallel, the student will work with iPSCs generated from ALS patients carrying the C9ORF72 expansion. These cells will be differentiated into motor neurons and other neural lineages. DNA methylation levels will be experimentally manipulated to assess downstream effects on gene expression, cellular stress responses, and motor neuron viability. This approach will allow direct testing of whether epigenetic modification alters disease-relevant cellular phenotypes.

The PhD student will receive comprehensive training in stem cell culture, molecular and epigenetic techniques, and quantitative data analysis. Day-to-day work will primarily involve laboratory-based experimentation and data interpretation, with opportunities to develop independence in experimental design and scientific communication. The project does not involve fieldwork, though funding may support attendance at national and international conferences and time spent at the co-supervisor's lab in Oxford, U.K.

This studentship will be based at the Royal Devon & Exeter Hospital campus within the Faculty of Health and Life Sciences at the University of Exeter, offering access to a collaborative research environment with close links to clinicians and neuroscientists. The project has strong translational relevance and will contribute to ongoing efforts to better understand the biological mechanisms underlying ALS.

Applicants should hold, or expect to obtain, a good honours degree (minimum 2:1 or equivalent) in neuroscience, biomedical sciences, genetics, molecular biology, or a related discipline. Previous laboratory experience is desirable but not essential, as full training will be provided.

The studentship covers Home tuition fees and provides a tax-free stipend of at least £22,000 per annum for 3.5 years (full-time), or pro rata for part-time study.

Please apply via the ‘Apply’ button above.