Investigating the oligogenic model of Amyotrophic Lateral Sclerosis (ALS; motor neuron disease, MND)

Applications are invited for a multidisciplinary PhD studentship funded by the Motor Neurone Disease Association to study the cumulative contribution of coinherited subthreshold amyotrophic lateral sclerosis (ALS) risk gene variants in the development of cellular hallmarks of ALS pathology. Successful candidate will be trained in cutting-edge bioinformatics and neurobiology techniques.

ALS is a fatal late-onset neurodegenerative disease affecting upper and lower motor neurons in the brain, brain stem and spinal cord. Despite the discovery of a number of ALS-associated genes, about 85% of cases are not caused by mutations in a single gene and thus, ALS is typically a complex disease. The risk of developing clinically manifest disease depends on the penetrance rate (the frequency with which a genotype manifests itself in a given phenotype) and the effect size (the effect of the genetic variant on the phenotype). Although the ALS-associated genetic variants are typically rare, they can exhibit variable penetrance with some carriers never developing the disease. Penetrance increases with age in ALS and the variability in penetrance can be caused by the presence of other genotypes, epigenetic factors, and lifestyle. It is therefore thought that the cause of non-familial cases of ALS has a significant genetic component, perhaps multiple uncommon variants with moderate effect size (oligogenic) or a large number of common variants (polygenic).

This project will test the oligogenic hypothesis of ALS onset by identifying subthreshold variants of ALS-associated proteins, focusing on those involved in autophagy, ubiquitin-proteasome system (UPS), and axonal transport to model and analyse their co-inheritance in motor neurons derived from CRISPR-Cas9 edited human induced pluripotent stem cells (iPSCs). By focusing on the autophagy/UPS/axonal transport proteostasis regulation axis, this project promises to potentially provide much needed experimental evidence for the oligogenic model of ALS onset using the clearance of pathogenic aggregated protein inclusions as a readout for the disease cellular pathophysiology. It could also provide a platform for development of high throughput screening strategies for identifying disease modifying drugs for treating ALS.

This multidisciplinary project will utilise methods at the forefront of human genome sequence analysis (bioinformatics) combined with CRISPR-Cas9 genome editing technology to create human iPSCs harbouring combinations of the subthreshold ALS-associated variants. These iPSC lines will then be differentiated into motor neurons and analysed for ALS pathology using a range of cellular and molecular neurobiology and advanced fluorescence microscopy techniques.

Applications are particularly welcomed from candidates with protected characteristics – e.g. from Black and other ethnic minorities – who are under-represented in postgraduate research at our institutions.

How to apply:

Please submit a formal application using the online system at www.sussex.ac.uk/study/phd/apply attaching a CV, degree transcripts and certificates, statement of interest and two academic references.

On the application system select Programme of Study – PhD Neuroscience. Please ensure you state the project title under funding and include the proposed supervisor’s name where required.

Ideal candidates will have a strong background in cellular and molecular biology with additional experience of bioinformatics.

Eligible candidates will have recently received an MSc and/or a First or 2:1 BSc in a relevant subject.

Candidates for whom English is not their first language will require an IELTS score of 6.5 overall, with not less than 6.0 in any section.

For enquiries about the project, contact supervisors: Professor Majid Hafezparast (m.hafezparast@sussex.ac.uk) or Dr Johnathan Cooper-Knock (j.cooper-knock@sheffield.ac.uk).