MRC DiMeN Doctoral Training Partnership: Using AI to predict amyloid aggregation in neurodegenerative diseases

Neurodegenerative diseases of ageing such as Alzheimer’s and Parkinson’s diseases (AD and PD) have a huge societal and financial impact yet cost-effective therapies to delay or cure these diseases are lacking. Traditional methods for studying the mechanisms of aggregation of the culprit proteins (Ab42 in AD and a-synuclein (AS) in PD) are complex, requiring the purification and characterisation of experimentally challenging proteins. How and why sequence modifications affect disease remain obscure, especially given the emerging importance of the synergistic co-aggregation of two or more proteins in AD and PD (AS and Ab42) and in Amyotrophic Lateral Sclerosis (AS and TDP-43). This complexity can be deciphered using machine learning (ML) and artificial intelligence (AI) but this requires large amounts of data linking the genotype to the observed phenotype. We have integrated an in vivo screen for protein aggregation [1][2] into a deep mutational scanning (DMS) platform[3]. Using this method, we have shown that the aggregation potential of every single-residue variant of Ab42 (~800 proteins) can be quantified in just a few days, opening the door to generating transformative understanding of amyloid formation.  

You will build on our exciting new approach by applying the screen to AS and TDP-43 when expressed separately and together. You will then use these datasets and AI/ML to generate predictive models for amyloidogenecity focussing on the unmet need of synergistic co-aggregation in neurodegeneration.  

This will be achieved by using molecular biological, biochemical, structural and data science methods: variant libraries will be created using error-prone PCR and fitness scores calculated via next generation sequencing using lab. protocols. ML/AI will be trained on these data to generate predictive models for amyloid formation and validated using biochemical, amyloid growth kinetics and structural analysis (cryoEM) of selected variants. 

The project will be supervised by Professor David Brockwell and Professor Sheena Radford FRS.  These groups (RadfordLab – X.com) share an integrated laboratory space with weekly science progress meetings, journal clubs and to annual research retreats.  Expertise available across the groups is exceptional spanning cell biology, microbiology, biophysics, biochemistry and molecular biology and a range of structural techniques including NMR, MS and EM provided a rich training environment. 

David Brockwell: https://biologicalsciences.leeds.ac.uk/molecular-and-cellular-biology/staff/38/professor-david-brockwell 

Sheena Radford: https://biologicalsciences.leeds.ac.uk/biological-sciences/staff/127/professor-sheena-radford 

Benefits of being in the DiMeN DTP: 

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of-the-art facilities to deliver high impact research. 

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors. 

Being funded by the MRC means you can access additional funding for research placements, training opportunities or internships in science policy, science communication and beyond. Further information on the programme and how to apply can be found on our website: 

https://www.dimen.org.uk/