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MRC Prion Unit
From fundamental research to prevention and cure

Structure and dynamics of prions and their ligand interactions

We aim to understand the central problem in the prion mechanism; what is the change in shape that distinguishes normal prion protein, PrP C , from its rogue form, PrP Sc , and how does it come about? Specifically, we are asking what the structural causes are for becoming a prion, and what the common drivers are for their replication. We are also trying to find out, whether the same principles underlie other diseases, both inside the central nervous system and in the rest of the body. 

The team works mainly with the human prion protein itself - which is synthetically produced in the Unit in large quantities (using genetically engineered bacteria) in a specially-designed laboratory. We combine a range of biophysical techniques with sophisticated nanoscopic imaging to study the structure, folding and dynamics of prions, both in isolation and also with likely binding partners, in order to develop new strategies in combatting prion diseases. 

The Unit recently discovered that a single amino acid change in the prion protein (glycine 127 to valine) completely protects the organism against prion disease. This mutation was discovered in Papua New Guinea, where the prion disease Kuru had been transmitted from human to human during burial rituals of Kuru-infected individuals.  Our group aims to understand the structural basis of this astounding protective effect of the single amino acid replacement. Under the lead of the late Tony Clarke († 2016), the program analysed the structure of the prion protein and its mutants by nuclear magnetic resonance (NMR) and protein crystallography to find out whether a change in shape of the prion protein is responsible for the protection against prion disease (Figure. 1). Jan Bieschke is leading the program since early 2018. Under his leadership, the group is complementing structural studies with analyses of the dynamics of the prion protein and its prion replication by a spectrum of biophysical methods.


Figure 1: Structure of mutant PrP (119-231, G127V) that we co-crystallized with an anti-prion antibody fragment (ICSM18). PrP is shown in green with the heavy and light chains of the antibody fragment in cyan and magenta, respectively.

The self-association of prion protein, which underlies prion disease pathology, proceeds via multiple intermediate stages. These oligomeric intermediates of PrP (and likewise of other proteins like amyloid-β, tau, and α-synuclein in Alzheimer’s and Parkinson’s disease) may be of crucial importance in the progress of the disease and in the toxicity to neurons. Our group is currently exploring the structural properties of oligomeric and fibrillary assemblies of PrP and other amyloidogenic proteins, as well as the transitions between these structures.

Figure 2: Transient amyloid binding (TAB) imaging. resolves amyloid structures at a nanometer scale using standard probes, Thioflavin T (ThT), without the need for covalent modification or immunostaining of amyloid structures by using the binding dynamics of ThT to generate super-resolution images (Spehar et al. 2018).

Traditional methods of structural biology yield highly resolved structural information, but are not well suited to monitor changes in structure in real time. We have developed a tool to observe amyloid structures over extended times by nanoscopic imaging. By exploiting the dynamics of transient amyloid binding (TAB) of dye molecules, we can image single binding events of the dye and reconstruct a nanoscopic image from the localizations of these single ‘blinks’ (Figure 2). This approach allows us to image the formation and degradation of amyloid-β, α-synuclein, PrP, tau and other amyloid structures by super-resolution microscopy in real time (Figure 3).

The combination of structural and kinetic measurements will allow us to scrutinize the mechanism of prion diseases on a fundamental level and to develop new diagnostic and therapeutic strategies to combat these devastating diseases.

Figure 3: Real time TAB imaging of Aβ42 fibril remodelling by the anti-amyloid compound epi-gallocatechin gallate (EGCG; scale bar 200 nm; image from Spehar et al. 2018)

Peer reviewed articles:

A.R. Clarke


Oral prion neuroinvasion occurs independently of PrPC expression in the gut epithelium.
Marshall A, Bradford BM, Clarke AR, Manson JC, Mabbott NA. J Virol. 2018


Physical, chemical and kinetic factors affecting prion infectivity.
Properzi F, Badhan A, Klier S, Schmidt C, Klöhn PC, Wadsworth JD, Clarke AR, Jackson GS, Collinge J. Prion. 2016


A systematic investigation of production of synthetic prions from recombinant prion protein.
Schmidt C, Fizet J, Properzi F, Batchelor M, Sandberg MK, Edgeworth JA, Afran L, Ho S, Badhan A, Klier S, Linehan JM, Brandner S, Hosszu LL, Tattum MH, Jat P, Clarke AR, Klöhn PC, Wadsworth JD, Jackson GS, Collinge J.Open Biol. 2015


N-terminal domain of prion protein directs its oligomeric association.
Trevitt CR, Hosszu LL, Batchelor M, Panico S, Terry C, Nicoll AJ, Risse E, Taylor WA, Sandberg MK, Al-Doujaily H, Linehan JM, Saibil HR, Scott DJ, Collinge J, Waltho JP, Clarke AR. J Biol Chem. 2014 

Prion neuropathology follows the accumulation of alternate prion protein isoforms after infective titre has peaked.
Sandberg MK, Al-Doujaily H, Sharps B, De Oliveira MW, Schmidt C, Richard-Londt A, Lyall S, Linehan JM, Brandner S, Wadsworth JD, Clarke AR, Collinge J. Nat Commun. 2014

J. Bieschke


Super-Resolution Imaging of Amyloid Structures over Extended Times Using Transient Binding of Single Thioflavin T Molecules.
Spehar K, Ding T, Sun Y, Kedia N, Lu J, Nahass GR, Lew MD, Bieschke J. Chembiochem. 2018


Glucose directs amyloid-beta into membrane-active oligomers.
Kedia N, Almisry M, Bieschke J. Phys Chem Chem Phys. 2017


Aggregation of Full-length Immunoglobulin Light Chains from Systemic Light Chain Amyloidosis (AL) Patients Is Remodeled by Epigallocatechin-3-gallate.
Andrich K, Hegenbart U, Kimmich C, Kedia N, Bergen HR 3rd, Schönland S, Wanker E, Bieschke J. J Biol Chem.  2016

Amyloid-β(1-42) Aggregation Initiates Its Cellular Uptake and Cytotoxicity.
Jin S, Kedia N, Illes-Toth E, Haralampiev I, Prisner S, Herrmann A, Wanker EE, Bieschke J. J Biol Chem. 2016

Stabilization of α-Synuclein Fibril Clusters Prevents Fragmentation and Reduces Seeding Activity and Toxicity.
Lam HT, Graber MC, Gentry KA, Bieschke J. Biochemistry. 2016


The Effect of (-)-Epigallo-catechin-(3)-gallate on Amyloidogenic Proteins Suggests a Common Mechanism.
Andrich K, Bieschke J. Adv Exp Med Biol.  2015

Tau Trimers Are the Minimal Propagation Unit Spontaneously Internalized to Seed Intracellular Aggregation.
Mirbaha H, Holmes BB, Sanders DW, Bieschke J, Diamond MI. J Biol Chem. 2015

The green tea polyphenol (-)-epigallocatechin gallate prevents the aggregation of tau protein into toxic oligomers at substoichiometric ratios.
Wobst HJ, Sharma A, Diamond MI, Wanker EE, Bieschke J. FEBS Lett. 2015

Major external collaborations:

Professor Matthew D Lew
Department of Electrical & Systems Engineering, Washington University in St Louis

Professor Conrad C Weihl,
Washington University in St Louis Medical School

Professor Jonathon P Waltho,
Biomolecular NMR, University of Sheffield

Professor Helen Saibil,
Department of Crystallography, Birkbeck College and Institute of Structural Molecular Biology, University of London

Dr. Katherine McAuley,
Diamond Light Source, Harwell Campus, Oxfordshire

Professor Ian Collinson,
Department of Biochemistry, University of Bristol

Dr Richard Sessions,
Department of Biochemistry, University of Bristol

Professor Mervyn Miles,
Centre for Nanoscience and Quantum Information, University of Bristol

Professor Leo Brady,
Department of Biochemistry, University of Bristol 

Dr David Scott,
National Centre for Macromolecular Hydrodynamics, University of Nottingham