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MRC Prion Unit
From fundamental research to prevention and cure
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Molecular and phenotypic analysis of prion strains

Prions, the infectious agents causing BSE in cows and 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. Our research focuses on isolating infectious prion particles from diseased tissue and using sophisticated equipment to study their chemical makeup and three-dimensional structure. 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 model prion strains from mice 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 person’s 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. Recently using new methods that we developed we were able to obtain the first three-dimensional images of isolated prions and we are now concentrating on using these techniques to find differences between prion strains.
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 vCJD has a distinct molecular and neuropathological phenotype in human brain. Scale bars 50 µm.

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Electron microscopy images of prions purified from mouse brain. Scale bars 50 nm.

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vCJD has a peripheral pathogenesis distinct from classical forms of CJD, with a prominent involvement of lymphoreticular tissues


Reviews:

Prions of Vertebrates. In: Reference Module in Biomedical Sciences, Elsevier. Wadsworth, J.D.F. and Collinge, J. (2014) doi:10.1016/B978-0-12-801238-3.02648-9

Molecular pathology of human prion disease
Wadsworth JDF, Collinge J. Acta Neuropathol 2011; 121: 69-77.

Contribution of transgenic models to understanding human prion disease
Wadsworth JDF, Asante EA, Collinge J.  Neuropathol App Nerobiol 2010; 36: 576-97.


Peer reviewed articles:
2018

Evaluating the causality of novel sequence variants in the prion protein gene by example.
Mok TH, Koriath C, Jaunmuktane Z, Campbell T, Joiner S, Wadsworth JDF, Hosszu LLP, Brandner S, Parvez A, Truelsen TC, Lund EL, Saha R, Collinge J, Mead S. Neurobiol Aging. 2018 May 15. pii: S0197-4580(18)30167-2. doi: 10.1016/j.neurobiolaging.2018.05.011. [Epub ahead of print] PMID:29861043

Experimental sheep BSE prions generate the vCJD phenotype when serially passaged in transgenic mice expressing human prion protein. Joiner S, Asante EA, Linehan JM, Brock L, Brandner S, Bellworthy SJ, Simmons MM, Hope J, Collinge J, Wadsworth JDF. J Neurol Sci. 2018 Mar 15;386:4-11. doi: 10.1016/j.jns.2017.12.038. Epub 2017 Dec 29. PMID:29406965

2017

Soluble Aβ aggregates can inhibit prion propagation.
Sarell CJ, Quarterman E, Yip DC, Terry C, Nicoll AJ, Wadsworth JDF, Farrow MA, Walsh DM, Collinge J. Open Biol. 2017 Nov;7(11). pii: 170158. doi: 10.1098/rsob.170158. PMID:29142106

Methods for Molecular Diagnosis of Human Prion Disease.
Wadsworth JDF, Adamson G, Joiner S, Brock L, Powell C, Linehan JM, Beck JA, Brandner S, Mead S, Collinge J. Methods Mol Biol. 2017;1658:311-346. doi: 10.1007/978-1-4939-7244-9_22. PMID:28861799

Variant Creutzfeldt-Jakob Disease in a Patient with Heterozygosity at PRNP Codon 129.
Mok T, Jaunmuktane Z, Joiner S, Campbell T, Morgan C, Wakerley B, Golestani F, Rudge P, Mead S, Jäger HR, Wadsworth JD, Brandner S, Collinge J. N Engl J Med. 2017 Jan 19;376(3):292-294. doi: 10.1056/NEJMc1610003. No abstract available. PMID:28099827

2016

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 May 3;10(3):251-61. doi: 10.1080/19336896.2016.1181250. PMID:27282252

Ex vivo mammalian prions are formed of paired double helical prion protein fibrils.
Terry C, Wenborn A, Gros N, Sells J, Joiner S, Hosszu LL, Tattum MH, Panico S, Clare DK, Collinge J, Saibil HR, Wadsworth JD. Open Biol. 2016 May;6(5). pii: 160035. doi: 10.1098/rsob.160035. Epub 2016 May 4. PMID:27249641

Clinical Trial Simulations Based on Genetic Stratification and the Natural History of a Functional Outcome Measure in Creutzfeldt-Jakob Disease.
Mead S, Burnell M, Lowe J, Thompson A, Lukic A, Porter MC, Carswell C, Kaski D, Kenny J, Mok TH, Bjurstrom N, Franko E, Gorham M, Druyeh R, Wadsworth JD, Jaunmuktane Z, Brandner S, Hyare H, Rudge P, Walker AS, Collinge J. JAMA Neurol. 2016 Apr;73(4):447-55. doi: 10.1001/jamaneurol.2015.4885.PMID:26902324

2015

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 Dec; 5(12). pii: 150165. doi: 10.1098/rsob.150165.

Iatrogenic CJD due to pituitary-derived growth hormone with genetically determined incubation times of up to 40 years
Rudge, P., Jaunmuktane, Z., Adlard, P., Bjurstrom, N., Caine, D., Lowe, J., Norsworthy, P., Hummerich, H., Druyeh, R., Wadsworth, J.D.F., Brandner, S., Hyare, H., Mead, S. and Collinge, J. Brain 138, 3386-3399.

Evidence for human transmission of amyloid ß pathology and cerebral amyloid angiopathy Zane Jaunmuktane, Simon Mead, Matthew Ellis, Jonathan D. F. Wadsworth, Andrew J. Nicoll, Joanna Kenny,Francesca Launchbury, Jacqueline Linehan, Angela Richard-Loendt, A. Sarah Walker, Peter Rudge, John Collinge & Sebastian Brandner

Transmission Properties of Human PrP 102L Prions Challenge the Relevance of Mouse Models of GSS. Asante EA, Grimshaw A, Smidak M, Jakubcova T, Tomlinson A, Jeelani A, Hamdan S, Powell C, Joiner S, Linehan JM, Brandner S, Wadsworth JD, Collinge J

A novel and rapid method for obtaining high titre intact prion strains from mammalian brain  Adam Wenborn, Cassandra Terry, Natalie Gros, Susan Joiner, Laura D’Castro, Silvia Panico, Jessica Sells, Sabrina Cronier, Jacqueline M. Linehan, Sebastian Brandner, Helen R. Saibil, John Collinge & Jonathan D. F. Wadsworth

A naturally occurring variant of the human prion protein completely prevents prion disease   Emmanuel A. Asante, Michelle Smidak, Andrew Grimshaw1, Richard Houghton, Andrew Tomlinson, Asif Jeelani, Tatiana Jakubcova, Shyma Hamdan, Angela Richard-Londt, Jacqueline M. Linehan, Sebastian Brandner, Michael Alpers, Jerome Whitfield, Simon Mead, Jonathan D.F. Wadsworth and John Collinge

2014

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

N-terminal domain of prionprotein directs its oligomeric association
Trevitt C, Hosszu L, Batchelor M, Panico S, Terry C, Nicoll A, Risse E, Taylor W, Sandberg M, Al-Doujaily H, Linehan J, Saibil H, Scott D, Collinge J, Waltho J, Clarke A. 
Journal of Biological Chemistry. 2014, Jul 29.Epub ahead of print. . 

mGlu5 receptors and cellular prion protein mediate amyloid-β facilitation of synaptic long-term depression in vivo
Hu NW, Nicoll A, Zhang D, Mably A, O'Malley T, Purro S, Terry C, Collinge J, Walsh D, and Rowan M. Nat Commun 2014; 5: 3374.

Variant Creutzfeldt-Jakob disease with extremely low lymphoreticular deposition of prion protein
Mead S, Wadsworth JDF, Porter MC, Linehan J, Pietkiewicz W, Jackson GS, Brandner S, Collinge J.  JAMA Neurol 2014; 71: 340-3.

2013

A novel prion disease presenting with diarrhea and autonomic neuropathy
Mead S, Gandhi S, Beck J, Caine D, Gallujipali D, Carswell C, Hyare H, Joiner S, Ayling H, Lashley T, Linehan JM, Al-Doujaily H, Sharps B, Revesz T, Sandberg M, Reilly M, Koltzenburg M, Forbes A, Rudge P, Brandner S, Warren JD, Wadsworth JDF, Wood NW, Holton JL, Collinge J.  New Eng J Med 2013; 369: 1904-14.

Inherited Prion Disease A117V is not simply a proteinopathy but produces prions transmissible to transgenic mice expressing homologous prion protein
Asante EA, Linehan JM, Smidak M, Tomlinson A, Grimshaw A, Jeelani A, Jakubcova T, Hamdan S, O’Malley C, Powell C, Brandner S, Wadsworth JDF, Collinge J.  PLoS Pathog 2013; 9: e1003643.

Atypical scrapie prions from sheep fail to produce disease in transgenic mice overexpressing human prion protein.
Wadsworth JDF, Joiner S, Linehan JM, Balkema-Buschmann A, Spiropoulos J, Simmons MM, Griffiths PC, Groschup MH, Hope J, Brandner S, Asante EA, Collinge J. Emerg Infect Dis 2013; 19: 1731-39.

Amyloid-β nanotubes are associated with prion protein dependent synaptotoxicity.
Nicoll AJ, Panico S, Freir D, Wright D, Terry C, Risse E, Herron CE, O’Malley T, Wadsworth J, Farrow M, Walsh D, Saibil HR, Collinge J.  Nat Commun 2013; 4: 2416. 

Sod1 deficiency reduces incubation time in mouse models of prion disease
Akhtar S, Grizenkova J, Wenborn A, Hummerich H, Fernandez de Marco M, Brandner S, Collinge J, Lloyd SE.  PLoS One 2013; 8: e54454.

Filamentous white matter prion protein deposition is a distinctive feature of multiple inherited prion diseases
Reiniger L, Mirabile I, Lukic A, Wadsworth JDF, Linehan JM, Groves M, Lowe J, Druyeh R, Rudge P, Collinge J, Mead S, Brandner S. Acta Neuropathol Comm 2013; 1: 8.

2012

Overexpression of Hspa13 (Stch) reduces prion disease incubation time in mice
Grizenkovaa J, Akhtara S, Hummerich H, Tomlinson A, Asante E, Wenborn A, Wiseman FK, Fisher EMC, Tybulewiczc VL, Brandner S, Collinge J, Lloyd SE. Proc Natl Acad Sci USA 2012; 109: 13722-7.

2011

Sex effects in mouse prion disease incubation time
Akhtar S, Wenborn A, Brandner S, Collinge J, Lloyd SE. PLoS One 2011; 6: e28741.

Inherited prion disease with 4-octapeptide repeat insertion: disease requires the interaction of multiple genetic risk factors
Kaski DN, Pennington C, Beck J, Poulter M, Uphill J, Bishop MT, Linehan JM, O'Malley C, Wadsworth JDF, Joiner S, Knight RSG, Ironside JW, Brandner S, Collinge J, Mead S.  Brain 2011; 134: 1829-1838.

Effect of fixation on brain and lymphoreticular vCJD prions and bioassay of key positive specimens from a retrospective vCJD prevalence study
Wadsworth JDF, Dalmau-Mena I, Joiner S, Linehan J, O'Malley C, Powell C, Brandner S, Asante EA, Ironside JW, Hilton DA, Collinge J.  J Pathol 2011; 223: 511-8.

2010

Isolation of proteinase K-sensitive prions using pronase E and phosphotungstic acid
D’Castro L, Wenborn A, Gros N, Joiner S, Cronier S, Collinge J, Wadsworth JDF. PLoS One 2010; 5: e15679.

Heterozygosity at polymorphic codon 219 in variant Creutzfeldt-Jakob disease.
Lukic A, Beck JA, Joiner S, Fearnley J, Sturman S, Brandner S, Wadsworth JDF, Collinge J, Mead S.  Arch Neurol 2010; 67: 1021-3.

Spontaneous generation of mammalian prions
Edgeworth J, Gros N, Alden J, Joiner S, Wadsworth JDF, Linehan J, Brandner S, Jackson GS, Weissmann C, Collinge J.  Proc Natl Acad Sci USA 2010; 107: 14402-6.

Chronic wasting disease prions are not transmissible to transgenic mice over-expressing human prion protein
Sandberg MK, Al-Doujaily H, Sigurdson CJ, Glatzel M, O’Malley C, Powell C, Asante EA, Linehan JM, Brandner S, Wadsworth JDF, Collinge J.  J Gen Virol 2010; 91: 2651-7.

2009

Absence of spontaneous disease and comparative prion susceptibility of transgenic mice expressing mutant human prion proteins
Asante EA, Gowland I, Grimshaw A, Linehan JM, Smidak M, Houghton R, Osiguwa O, Tomlinson A, Joiner S, Brandner S, Wadsworth JD, Collinge J.  J Gen Virol 2009; 90: 546-58.

Seven year discordance in age at onset in monozygotic twins with inherited prion disease (P102L)
Webb T, Mead S, Beck J, Uphill J, Pal S, Hampson S, Wadsworth JD, Mena ID, O'Malley C, Brandner S, Schapira A, Wroe S, Collinge J.  Neuropathol Appl Neurobiol 2009; 35: 427-32.

 


Book chapters:

Prions of Vertebrates. In: Caplan MJ, ed. Reference Module in Biomedical Sciences.
Wadsworth JDF, Collinge J.  Elsevier, in press, 2014.

Molecular basis of prion diseases.
Wadsworth JDF and Collinge J.  In: Siegel JR, Albers RW, Brady ST, Price DL, eds. Basic Neurochemistry, 8th edn. Elsevier Academic Press, San Diego, California, USA, 2012; 791-803.


Published abstracts:

Novel truncation mutation of PRNP causes chronic diarrhoea, sensory neuropathy and autonomic failure associated with prion protein deposition in the cerebral blood vessels and small bowel.
Mead S, Linehan J, Beck J, Caine D, Gandhi S, Wadsworth JDF, Joiner S, Gallujipali D, Hyare H, Lees A, Holton J, Sandberg M, Revesz T, Carswell C, Warren JD, Collinge J & Wood N.  J Neurol
Neurosurg Psychiatry 2010; 81: e24 doi:10.1136/jnnp.2010.226340.31.

Misleading MRI in two recent patients with variant Creutzfeldt–Jakob disease emphasises the importance of tissue diagnosis.
Lukic A, Wadsworth J, Brandner S, Rudge P, Hyare H, Collinge J, Reiniger L, Mead S, Gilmore C, Humberstone M. (2010) J Neurol Neurosurg Psychiatry 2010; 81, e42 doi:10.1136/jnnp.2010.226340. 101.

Novel truncation mutation of PRNP causes chronic diarrhoea, sensory neuropathy and autonomic failure associated with prion protein deposition in the cerebral blood vessels and small bowel.
Mead S, Gandhi S, Carswell C, Ayling H, Beck J, Caine D, Gallujipali D, Hyare H, Joiner S, Lees AJ, Linehan J, Revesz T, Sandberg M, Wadsworth JDF, Warren JD, Wood NW, Holton J & Collinge J. Prion 2010; 4: 201.

Spontaneous formation of prions in brain tissue
Edgeworth JA, Gros N, Alden J, Joiner S, Wadsworth J, Linehan J, Brandner S, Jackson G, Weissmann C & Collinge J.  Prion 2010; 4: 140.

Heterozygosity at polymorphic codon 219 in two variant Creutzfeldt-Jakob disease patients
Lukic A, Beck J.A, Wadsworth JDF, Brandner S, Collinge J & Mead S.
J Neurol Neurosurg Psychiatry 2009; 80: e1.