NEURONODE: Using novel stem cell models to understand the regulation of translation in neurodegenerative diseases

According to the WHO, neurological disorders comprised 3% of the total global burden of disease. In the UK alone, around 1 million people suffer from a neurodegenerative disorder (ND). The global cost of mental health conditions alone is estimated at US$2.5 trillion, and projected to double by 2030. There is thus an urgent need for new biomarkers for detection and therapeutic targets in the development of curative drugs, and not just treating the symptoms. Neurodegenerative disorders affecting the ageing population are characterized by the loss of specific neuronal cells, which can be triggered by alterations in protein homeostasis and changes in mRNA translation. This typically result in reduced protein synthesis or translation to increase the cellular capacity for protein folding and degradation.

Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic lateral sclerosis (ALS) are NDs with proteostasis defects. They represent an ideal set of diseases covering >70% of patients to increase our understanding of the molecular basis of NDs. The associated pathologies are difficult to truly model and compare using animals because (i) they are mainly caused by sporadic forms of the diseases, and (ii) models do not recapitulate the basic cellular changes observed in patients. Our aim is to achieve a global understanding of RNA translation and stress granules regulation across these neurodegenerative diseases using novel genetically engineered isogenic human stem cell lines. This will identify key regulatory nodes, across diseases, revealing new points for therapeutic interventions.

The PhD candidate will work as part of an EU/MRC-funded trans-national consortium that has developed control fibroblasts genetically engineered into disease cell lines (project grant MR/R02426X/1), allowing studies within identical genetic backgrounds. Following training with our project partners at McGill (Canada) and QMUL (UK), the control and disease-model iPSCs will be used to differentiate neuronal cell populations including forebrain cortical-like neurons, midbrain dopamine-like and glial astrocyte-like cells. Subsequently, the candidate will be trained in confocal microscopy techniques to detect and quantity stress granules in cells, measure translational activity globally and specifically at the mRNA level using ribosomes profiling.

Applicants are expected to hold a good honours degree (upper second) in an appropriate discipline, but prior experience in research or industry may be acceptable. Enthusiasm for, and commitment to, independent study is essential.