Unravelling the molecular mechanisms of amyotrophic lateral sclerosis / motor neuron disease

• 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.