
Dr. Szymon W. Manka
Grant Title: Engineering human cells to propagate fluorescent prions for live monitoring of prion infection and high-resolution in situ prion structure determination
Location: Imperial College London, Faculty of Medicine, Department of Infectious Disease, Synthetic and Structural Biology Section
Grant Year: 2025
Location: Imperial College London, Faculty of Medicine, Department of Infectious Disease, Synthetic and Structural Biology Section
Grant Year: 2025
The accumulation of prions in the brain causes nerve cells to die, but the disease mechanisms at play, often active decades before clinical symptoms appear, remain unclear. Identifying and characterizing the molecular pathways involved in disease progression could pave the way for designing novel anti-prion therapeutics. This project aims to engineer human cells to produce fluorescent (glowing) prions. By infecting these cells with authentic prions isolated from terminally sick animals, we hope to visualize and track prions within the complex environment of living cells. This will allow us to study all stages of prion propagation: uptake, growth, replication, and transport within and between cells, using advanced microscopic techniques. Making prions visible without disrupting the processes governing their propagation and toxicity is challenging. With this funding, we aim to refine a novel approach that uses genetic manipulation of lab-grown human cells. This prion-labeling method will be combined with cryogenic correlated light and electron microscopy (cryo-CLEM), which uses fluorescent signals to pinpoint prions in specific cellular compartments. It will enable us to map the cellular sites of prion propagation and examine the various prion structures formed there with unprecedented resolution. Ultimately, we aim to identify and characterize key cellular mediators or interaction partners that drive prion pathogenicity during distinct stages of infection.
About the Researcher:
Dr Szymon W. Manka is an expert in cryogenic electron microscopy and advanced image processing algorithms for 3D reconstruction of macromolecular structures at near-atomic resolution. He recently introduced genetic code expansion and bioorthogonal labelling techniques to develop and expand the structural cell biology toolbox for prion research. Szymon leads a prion research lab at Imperial College London. His current research is funded by the UK Medical Research Council and the CJD Foundation.