Molecular and phenotypic analysis of human prion strains

Lead Research Organisation: MRC Prion Unit

Abstract

Prions, the infectious agents causing BSE in cows and variant CJD in humans are unique in medical research. Unlike all other infectious agents (bacteria and viruses) the infectious particle does not contain genetic information (genes) but instead consists of a protein (called PrPSc). Although prions do not carry genetic material they come in several different forms, called prion strains that cause different forms of the disease. Our research aims to understand the fundamental biology of what makes prion strains different from one another and why some are able to cross from animals to humans to cause disease. Understanding these differences is vital to providing early diagnosis and to developing effective cures that halt the spread of prion infection and prevent fatal brain damage.||Our research focuses on isolating infectious prion particles from diseased tissue and using sophisticated equipment to study their chemical makeup. Through these studies we aim to provide a detailed description of the protein (PrPSc) associated with each prion strain and pinpoint exactly what differences are responsible for a particular form of disease. For some studies we use a prion strain (RML prions) that can be detected in isolated cells allowing us to make much faster progress than has been previously possible. In other studies we use genetically altered mice (transgenic mice) to understand which animal prion strains may pose a risk to humans and to see what these diseases may look like should people become infected. These studies have confirmed that variant CJD is caused by the same prion strain that causes BSE in cows and have established that a persons genetic makeup may influence the type of prion disease they will develop if infected with BSE prions.||Because of the very long time periods possible between infection and the appearance of symptoms the number of people with BSE infection is unknown. This has raised fears that infected people who have no signs of the disease might pass it on to others by surgery, blood transfusion and other medical routes. We have pioneered laboratory tests to rapidly detect variant CJD and other forms of disease caused by BSE infection should they occur. Our findings have been used throughout the world to help accurately diagnose human prion diseases and have assisted the World Health Organisation to develop measures to limit the spread of these diseases from one person to another by medical procedures.

Technical Summary

Prion diseases are fatal neurodegenerative disorders that include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI), kuru and most recently variant CJD (vCJD) in humans. Their central feature is the conversion of a normal host protein, the cellular prion protein (PrPC), to an abnormal isoform, designated PrPSc. This transition appears to involve only conformational change rather than covalent modification and confers PrPSc with resistance to proteolytic degradation and detergent insolubility. The marked clinical heterogeneity observed in human prion diseases has yet to be explained. However, it has been clear for many years that distinct isolates, or strains, of prions can be propagated in the same host and these are biologically recognised by distinctive clinical and pathological features. It is therefore likely that a proportion of clinicopathological heterogeneity seen human prion diseases relate to the propagation of distinct human prion strains. How this strain diversity is encoded by an apparently protein-only agent remains one of the most interesting and challenging questions in biology. Although distinct mammalian prion strains are associated with different prion protein conformations and glycoform assembly states their precise composition and the molecular determinants of strain remain unknown. Our integrated series of research projects aim to define the molecular composition and ultra-structure of infectious prions and elucidate the molecular basis of prion strain diversity. Knowledge generated by this research is expected to have direct translational benefit by facilitating improved methods of diagnosis and therapeutic treatments for human prion disease.

Publications

10 25 50
 
Description Member of the UK Health Protection Agency Expert Advisory Group on the Laboratory Testing Strategy for Large Scale Abnormal Prion Prevalence Studies (2006-0ngoing).
Geographic Reach Asia 
Policy Influence Type Participation in advisory committee
URL http://europepmc.org/abstract/MED/19460798
 
Description Member of the UK and Irish Blood Transfusion Services Prion Working Group.
Geographic Reach Asia 
Policy Influence Type Participation in advisory committee
 
Description Member of the World Health Organisation International Expert Consultation Group for Tissue Infectivity Distribution in Transmissible Spongiform Encephalopathies
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
Impact Provision of worldwide guidance to help minimize or eliminate the risk for transmitting BSE and vCJD to humans via biologicals and other medicinal products. http://www.who.int/bloodproducts/cs/TSEPUBLISHEDREPORT.pdf
URL http://www.who.int/bloodproducts/cs/TSEPUBLISHEDREPORT.pdf
 
Description Transmission studies in humanised transgenic mice to investigate recent MV vCJD case
Amount £737,960 (GBP)
Funding ID NIHR Policy Research Programme PR-R17-0916-23002 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2018 
End 04/2021
 
Title Improved methods for diagnosis of prion disease 
Description Improvement of existing methods. Described in Wadsworth JDF, Powell C, Beck JA, Joiner S, Linehan JM, Brandner S, Mead S, Collinge J. (2008) Molecular diagnosis of human prion disease. Methods in Molecular Biology 459: 197-227. PMID:18576157 Cronier S, Gros N, Tattum H, Jackson GS, Clarke AR, Collinge J, Wadsworth JDF. Detection and characterization of proteinase K-sensitive disease related prion protein with thermolysin. Biochem J 2008; 416: 297-305. PMID:18684106 
Type Of Material Technology assay or reagent 
Year Produced 2008 
Provided To Others? Yes  
Impact Methods are in worldwide use to aid with diagnosis of human and animal prion disease. 
URL http://europepmc.org/abstract/MED/18576157
 
Description Investigation of Animal Prion Disease 
Organisation Norwegian Veterinary Institute
Country Norway 
Sector Private 
PI Contribution Collaborative investigation of the zoonotic potential of cervid chronic wasting disease prions from Norway
Collaborator Contribution Provision of cervid tissue samples
Impact One output so far. PMID: 33502474 Multidisciplinary involving biochemistry, transmission studies in mice and immunohistochemistry
Start Year 2016
 
Description Investigation of Prion Structure 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Lead experimental work on mass spectrometry of purified prions
Collaborator Contribution Expertise in mass spectrometry
Impact No outputs yet
Start Year 2017
 
Description Investigation of human prion disease 
Organisation Derriford Hospital
Department Histopathology
Country United Kingdom 
Sector Hospitals 
PI Contribution Investgation of human tissue samples
Collaborator Contribution Provision of tissue specimens and expert opinion
Impact PMID:21294124
Start Year 2006
 
Description Investigation of human prion disease 
Organisation Medical University of Vienna
Country Austria 
Sector Academic/University 
PI Contribution Collaborative research on human prion disease
Collaborator Contribution Provision of samples and neuropathological analysis
Impact PMID:16597650
Start Year 2006
 
Description Investigation of human prion disease 
Organisation University of Edinburgh
Department The National Creutzfeldt-Jakob Disease Research & Surveillance Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution Investigation of human tissue samples
Collaborator Contribution Provision of tissue specimens and expert opinion
Impact PMID:21294124
Start Year 2006
 
Description Investigation of ovine prions 
Organisation Animal Health And Veterinary Laboratories Agency (AHVLA)
Country United Kingdom 
Sector Public 
PI Contribution Transmission studies of natural prions from sheep
Collaborator Contribution Provision of biological materials and data
Impact Publications PMID:24188521, PMID: 29406965
Start Year 2007
 
Description Investigation of prion structure 
Organisation Birkbeck, University of London
Department Institute of Structural and Molecular Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution Generation of purified proteins for electron microscopy
Collaborator Contribution Electron microscopy
Impact PMID:24022506, PMID: 25950908, PMID: 27249641, PMID: 29142106, PMID: 30675000
Start Year 2010
 
Description Investigation of prion structure 
Organisation University of Bristol
Department School of Physics
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of purified prions
Collaborator Contribution Analyses by atomic force microscopy
Impact PMID: 30675000
Start Year 2017
 
Description John Donne Primary School, Peckham, London 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Interactive workshop
Year(s) Of Engagement Activity 2016
 
Description Workshop on how medicines work Royal Holloway Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Interactive presentation
Year(s) Of Engagement Activity 2015
 
Description A talk or presentation - Interaction with patients Centenary of the UK Medical Research Council, National Prion Clinic Open Day, London. 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Research talks about prion disease
Year(s) Of Engagement Activity 2013
 
Description Article for MRC Life 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Wrote an article called "Making science centre stage: Using performance art to communicate about neurodegeneration.
Year(s) Of Engagement Activity 2018
 
Description Article for patient group newsletter CJD Support Network 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Update on current research on prion diseases
Year(s) Of Engagement Activity 2017
URL http://www.cjdsupport.net/images/pdf/newsletter/2017_Newsletter_May.pdf
 
Description Biochemical Society 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Blog article written to summarise public engagement activities with schools.
Year(s) Of Engagement Activity 2017
 
Description Botanic Gardens Conservation International 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Blog article written about developing educational systems.
Year(s) Of Engagement Activity 2017
URL https://www.bgci.org/about-us/index
 
Description Brighton Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Workshop teaching children about doping in sports, including an investigation and experiment to determine whether a group of fictional athletes were guilty of using performance enhancing drugs.
Year(s) Of Engagement Activity 2018
URL http://www.brightonscience.com/
 
Description British Brain Bee Competition 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Acted as scientific advisors for British Brain Bee we were asked to write exam questions for the neuroscience competition on 17th March 2018.
Year(s) Of Engagement Activity 2017,2018
URL https://www.brainbee-uk.com/
 
Description British Brain Bee invited talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Gave a talk to the organisers and volunteers at British Brain Bee, a charity focused on promoting neuroscience to school children.
Year(s) Of Engagement Activity 2018
 
Description CJD Support Network Family Support Meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Attended meeting and gave a talk about latest research findings in prion structure. Discussion panel - answered science questions from family members who have been affected by CJD.
Year(s) Of Engagement Activity 2017
URL http://www.cjdsupport.net/
 
Description Dagenham Youth Parade 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Interactive stall about infectious agents at a fair as part of The Dagenham Youth Parade.
Year(s) Of Engagement Activity 2017
URL https://www.lbbd.gov.uk/event/youth-parade/
 
Description Henrietta Barnett School, Hampstead, London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Interactive presentation
Year(s) Of Engagement Activity 2016
 
Description Interaction with a patient group 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact PhD studentship receives an endowment from the CJD Support Network. Regular written and verbal research updates are provided to CJDSN. http://www.cjdsupport.net/UserFiles/File/CJD%20news%200408%20final%20print%20version.pdf http://www.cjdsupport.net/UserFiles/File/CJD%20news%200409.pdf

Provision of support to patients and families affected by CJD.
Year(s) Of Engagement Activity 2008,2009
 
Description Interaction with journalists 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Preparation of MRC press releases and interaction with journalists covering our research.

Interaction with the media led to the following web links covering our research http://news.bbc.co.uk/1/hi/health/6217296.stm http://news.bbc.co.uk/1/hi/health/7167866.stm http://www.mrc.ac.uk/Newspublications/News/MRC004444
Year(s) Of Engagement Activity 2006,2007,2008,2015
URL http://www.insight.mrc.ac.uk/2015/03/12/behind-the-picture-proving-the-link-between-bse-and-vcjd/
 
Description Interaction with patients 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Presentation to patients, policy-makers and healthcare professionals as part of the Centenary of the UK Medical Research Council. National Prion Clinic Open Day, London.

Positive written resonses from patients and family members
Year(s) Of Engagement Activity 2012
 
Description Member of the UK Health Protection Agency Expert Advisory Group on the Laboratory Testing Strategy for Large Scale Abnormal Prion Prevalence Studies (2006-0ngoing). 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Scientific advisor. Provision of research materials. Conducted support research.

Contribution to understanding the population prevalence of vCJD infection. Prevalence of disease related prion protein in anonymous tonsil specimens in Britain: cross sectional opportunistic survey. PMID: 19460798
Year(s) Of Engagement Activity 2006,2007,2008,2009
 
Description Member of the UK and Irish Transfusion Services Prion Working Group (2008-ongoing. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Health professionals
Results and Impact Scientific advisor.

Influence on healthcare policy decisions regarding the impact of vCJD to the blood transfusion service.
Year(s) Of Engagement Activity 2008,2009
 
Description Member of the World Health Organisation International Expert Consultation Group for Tissue Infectivity Distribution in Transmissible Spongiform Encephalopathies (2005-ongoing) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Scientific advisor. Provided scientific data following an oral presentation at an international meeting at WHO Headquarters, Geneva in 2005. Contributed to resulting World Health Organisation guidelines in 2006.

Contributed to publication of World Health Organisation guidelines. http://www.who.int/bloodproducts/cs/TSEPUBLISHEDREPORT.pdf
Year(s) Of Engagement Activity 2006
URL http://www.who.int/bloodproducts/cs/TSEPUBLISHEDREPORT.pdf
 
Description Monken Hadley CE Primary School, Barnet, London 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact A school visit with interactive activities for children describing different types of infectious agents and also antibiotic resistance and good hygiene.
Year(s) Of Engagement Activity 2018
 
Description Neuroscience career talk UCL 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Career advice to secondary school children
Year(s) Of Engagement Activity 2016
 
Description Rokeby Educational Trust Ltd, Kingston Upon Thames, Surrey 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Interactive presentation
Year(s) Of Engagement Activity 2017
 
Description Royal Society of Biology's Biology Week, Hills Road 6th Form College, Cambridge 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Interactive presentation
Year(s) Of Engagement Activity 2015
 
Description Science Week sponsored by The Wellcome Trust 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Students from a secondary school sent in questions to the MRC Prion Unit for scientists to answer. We filmed a group of scientists from the Unit answering these questions and made a film for the students to watch at school.
Year(s) Of Engagement Activity 2017
 
Description Science careers fair St Marys and St Johns CE School, Barnet, London. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Interactive presentation
Year(s) Of Engagement Activity 2016
 
Description Springer Nature, London 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact Scientists performed on stage with poets and actors delivering a poem about prion diseases.
Year(s) Of Engagement Activity 2017
URL https://www.illingworthandsimpson.com/experimentalwords/
 
Description The Girls Network 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Meet with a student from a disadvantaged background on a monthly basis from 11/2017 - 11/2018. Provide careers advice and any advice about lessons, choosing universities, writing personal statements, job applications, etc.
Year(s) Of Engagement Activity 2017,2018
URL https://thegirlsnetwork.org.uk/
 
Description The Girls Network. Ark Elvin Academy, Wembley, London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Interactive discssion
Year(s) Of Engagement Activity 2016
URL https://thegirlsnetwork.org.uk/
 
Description The Wellcome Trust PhD Student Meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Acted as Panel Member at The Wellcome Trust at a meeting for new PhD students. Gave a presentation and answered questions.
Year(s) Of Engagement Activity 2017
 
Description UCL Institute of Neurology Work Experience Week 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Gave talk about prion research to A level students as part of UCL ION Work Experience Week.
Year(s) Of Engagement Activity 2017
 
Description UCL Network Event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Networking event where science communicators both within and outside academia came together at UCL to give talks and share ideas about their experiences in science communication.
Year(s) Of Engagement Activity 2017