MRC DiMeN Doctoral Training Partnership: Seeing inside the Parkinson’s disease brain by in situ cryo-ET

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are characterised by the accumulation and spread of ⍺-synuclein filaments in the brain. Roughly half of Alzheimer’s disease (AD) patients also harbour ⍺-synuclein deposits. The structure of ⍺-synuclein filaments and Lewy bodies in situ within fresh brain is currently unknown.  

The Frank group have recently developed methods for investigating structure and molecular mechanisms of proteins within cells and tissues by fluorescence-guided cryo-electron tomography (cryo-ET). For example, we determined the first in situ molecular architecture of β-amyloid in a mouse model of Alzheimer’s disease [1] and the first structure of a protein within AD human brain [2]. We are seeking a highly motivated PhD student to join our collaborative teams to investigate the ⍺-synuclein aggregates within Parkinson’s disease and Alzheimer’s disease brain. 

The methods used will include: i) Cryo-ET and computational image processing. ii) Cryo-focussed ion beam scanning electron microscopy (cryoFIB-SEM), cryo-sectioning, and cryogenic correlated light and electron microscopy (cryoCLEM). iii) Single-particle cryoEM. iv) Experiments with mouse models and post-mortem PD, DLB, and AD donor brain. v) Biochemical and genetic labelling. Applicants from all backgrounds, including biological, physical, chemical sciences, are encouraged to apply. Some experience with programming (e.g. Python, Matlab or similar) would be advantageous.  

This project will generate information-rich cryoET, integrating the molecular and cellular basis of disease for the first time. Thus, the student undertaking this research will receive an interdisciplinary training at the cutting edge of structural biology, neuroscience, and dementia research.  

Prospective PhD students are encouraged to send an informal email enquiry to r.frank@leeds.ac.uk in the first instance with a summary of what interests you about our research and any laboratory or computational experience to date. 

Frank Group website: https://sites.google.com/view/renefrankgroup/publications 

Radford Group website: https://sheena-radford-lab.uk/radford.php 

Ranson Group website: https://astbury.leeds.ac.uk/people/prof-neil-ranson-director/ 

Twitter/X: @drrenefrank @Radfordlab @naranson 

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/