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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

We are all familiar with the idea that infectious agents such as bacteria and viruses come in different types or “strains”. It is usually easy in the laboratory to identify the strain causing an outbreak, as each strain will have differences in its genetic material. Take the example of an outbreak of food poisoning. Public health doctors can isolate the germ and strain type it and then try to identify the common source from which people became infected. Although prions do not carry genetic material, they also come in several different forms - again known as strains. If prions are just proteins, how can they come in different strains? This has been a very important question. It is now clear that there is not just one rogue form of PrP that causes prion disease but there several distinct rogue forms. These different types of PrPSc can be identified by a laboratory test on a tissue sample, called a Western blot. Using these methods, Unit scientists identified four main types of PrPSc in the brain tissue of patients with the various forms of CJD in 1996. Types 1-3 were seen in “classical” CJD (sporadic and iatrogenic) – the forms of CJD we have known about for many years – while type 4 was unique to vCJD. This breakthrough has been very important not only in understanding the source of the vCJD outbreak, but is also now allowing us to classify other forms of CJD by its cause rather than just by clinical description. It is hoped this will cast new light on the origins of “sporadic” CJD – the precise cause of which is still unknown. Recent work from the Unit has shown that BSE prions can cause two distinct diseases in laboratory mice, one that looks like vCJD (with type 4 prions) and another form like sporadic CJD (with type 2 prions). Although we do not know yet if this has occurred in humans, we have to consider the possibility that BSE might cause other forms of prion disease in humans as well as vCJD. This is being intensively studied in the Unit currently.

Dr Jonathan Wadsworth and his team are aiming to achieve a fundamental understanding of the biochemical differences between prion strains. This is also of key importance in understanding how prions jump from one species to another. It turns out that the species barrier does not just depend on the species concerned but also on which strain of prion is involved. For example, classical CJD prions from MM patients do not readily infect laboratory mice but vCJD prions, also from MM patients, do.

Understanding strains may also be very important for treatment. We know that prion strains can switch from one to another type on infecting an animal and that animals can also be infected with multiple strains. It is therefore possible that prions may develop resistance to drugs (just as bacteria can become resistant to antibiotics) by changing strains.

Jon Wadsworth

Jonathan's team has also been working hard on better methods of detecting PrPSc which can be used for earlier diagnosis. Unit staff first showed in 1997 that PrPSc could be detected in tonsil tissue in vCJD and tonsil biopsy was consequently developed at the NPC as a method to allow firm and early diagnosis of vCJD. A positive tonsil biopsy has now been accepted as part of the National and World Health Organisation diagnostic criteria for vCJD. These methods are also now being used in large scale anonymous screening of discarded human tissue following tonsillectomy operations to try to estimate how much silent vCJD prion infection is present in the UK population.


Reviews:

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:
2015

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 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

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 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.

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