Cellular mechanisms of prion-mediated neurodegeneration

Lead Research Organisation: University College London
Department Name: UNLISTED

Abstract

The prion diseases are a group of rare but fatal diseases of the central nervous system (the brain in particular) for which there is at present no cure. They include CJD in humans, and scrapie and BSE in animals. These diseases can be acquired by ingestion of foodstuff containing the causative agent (called prion), for example contaminated meat and bone meal in the case of BSE, and products derived from cattle suffering from BSE in the case of variant CJD (vCJD). The BSE epidemic in the UK and the subsequent emergence of vCJD has made prion diseases a subject of intense research. BSE has no doubt transmitted to humans, but what is not known is what proportion of the exposed population will go on to develop vCJD. It is known that vCJD prions are transmitted by blood transfusion and currently there is concern that many of the UK population may be carrying vCJD prions which then may be transmitted through surgical procedures or blood transfusion. How prions cause damage to the nervous system is not known and the work in this study seeks to understand this. Once the key pathways have been defined then new drugs may be developed that act against those pathways. Other more common dementias such as Alzheimer?s disease and Parkinson?s disease may also share similar pathways to nerve cell death so understanding prion disease may also help identify treatment targets for these diseases.

Technical Summary

Prion diseases are fatal neurodegenerative disorders whose pathogenesis is associated with a conformational rearrangement of the normal cellular prion protein (PrPC) to abnormal conformers (PrPSc). How prions cause neuronal death is not known. We have recently published in vivo and in vitro experimental data suggesting a novel mechanism for intracellular neurotoxicity mediated by oligomers of misfolded PrP. This grant seeks funding to continue this work to unravel the pathways of prion protein trafficking and degradation and how these may be altered to result in prion-mediated neurotoxicity. Understanding the cellular pathways of prion protein trafficking is fundamental to address how the misfolded prion protein causes neuronal dysfunction and death. We will also study prion neurobiology in our novel vCJD prion propagating cell line and determine the time course of prion degradation and prion-mediated neurodegeneration in ageing human neurons. Following these pathways in a neuronal model close to the human in vivo situation will have clear benefits for the development of therapeutics aimed at enhancing degradation or clearance of human vCJD prions. This cell line will therefore also be useful for screening human prion therapeutics as to date no human cell models exist in which to screen human prion therapies. Understanding cellular mechanisms of neurodegeneration is of fundamental scientific interest and importance. Neurodegenerative diseases represent one of the biggest health problems in our ageing society, and uncovering basic molecular mechanisms is fundamental for the development of rational therapeutics. Many neurodegenerative diseases such as AD, PD and HD occur as a result of misfolding and aggregation of key cellular proteins (protein conformational disorders). Prion disease is the prototypical protein misfolding neurodegenerative disorder as its pathogenesis is only associated with aberrant misfolding of a host cellular protein (the protein-only hypothesis). Therefore, advances in understanding the pathophysiology of prion disease has major implications for other neurodegenerative diseases associated with protein misfolding as it may help elucidate common cellular mechanisms in neurodegeneration. In addition, although prion diseases are rare, there are currently significant public health concerns in the UK re secondary transmission of vCJD (the human form of BSE) and whether a significant number of the UK population are indeed subclinical carriers of prion disease. Therefore the work in this project will both have relevance for the understanding of neurodegeneration per se as well as yield new cellular models for screening of human prion therapeutics.

Publications

10 25 50
 
Description Brain Research Trust PhD Studentship
Amount £88,231 (GBP)
Organisation Brain Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2007 
End 03/2010
 
Description Celluar pathophysiology of prion mediated
Amount £607,672 (GBP)
Funding ID MR/J003832/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2012 
End 12/2016
 
Description Cure HD Initiative
Amount £115,561 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start 05/2010 
End 07/2010
 
Description Cure HD Initiative
Amount £151,962 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start 02/2010 
End 04/2010
 
Description Dissecting myeloid and neuronal interactions in HD
Amount £112,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 08/2011 
 
Description Dissection of Peripheral and Central Myeloid Cell Function in HD
Amount £60,442 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start 04/2010 
End 03/2011
 
Description Euro-HD Registry Project Manager/European Huntington's Disease Network
Amount £173,200 (GBP)
Organisation European Huntington's Disease Network (Euro-HD) 
Sector Charity/Non Profit
Country Germany
Start 01/2008 
End 02/2011
 
Description Muscle pathology in HD as a source for biomarkers
Amount £14,062 (GBP)
Organisation European Huntington's Disease Network (Euro-HD) 
Sector Charity/Non Profit
Country Germany
Start 03/2011 
 
Description Neuroendocrine profiling in Huntington's disease using meso-scale discovery
Amount £32,400 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start 06/2007 
End 07/2007
 
Description Peripheral innate immune system activation in Huntington's disease and delineation of its importance for disease pathogenesis and biomarkers
Amount £151,962 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2008 
End 12/2010
 
Description Pharmacodynamic Approaches to Demonstration of Disease-Modification in Huntington's Disease by SEN0014196 (PADDINGTON). EU FP7 Health Call
Amount £1,568,000 (GBP)
Funding ID 261358 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 06/2010 
End 12/2013
 
Description Prevalence of HD in the UK
Amount £15,000 (GBP)
Organisation Huntington's Disease Association England & Wales (HDA) 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description TRACK-HD
Amount £2,950,000 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start 04/2007 
End 03/2012
 
Description The use of microarray gene profiling in HD blood to identify potential surrogate disease biomarkers as an aid to development to therapies
Amount £52,000 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start 06/2006 
End 07/2007
 
Description UCL/UCLH Comprehensive Biomedical Research Centre PhD Studentship/UCL/UCLH Comprehensive Biomedical Research Centre
Amount £61,390 (GBP)
Organisation National Institute for Health Research 
Department UCLH/UCL Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 04/2009 
End 03/2012
 
Description Dr Maria Bjorkqvist 
Organisation Lund University
Country Sweden 
Sector Academic/University 
PI Contribution Intellectual contribution and reagents
Collaborator Contribution Intellectual contribution and reagents
Impact 18625748
Start Year 2006
 
Description Nico Dantuma Group 
Organisation Karolinska Institute
Department Department of Cell and Molecular Biology
Country Sweden 
Sector Academic/University 
PI Contribution Intellectual contribution and reagents
Collaborator Contribution Intellectual contribution and reagents
Impact Sarah has a paper with Nico Dantuma.  She says she has been collaborating with him from 2006: M Kristiansen, P Deriziotis, D Dimcheff, GS. Jackson, H Ovaa, H Naumann, F Leeuwen, V Benito, AR Clarke, NP Dantuma, JL Portis, J Collinge, SJ Tabrizi.  Disease associated prion protein oligomers inhibit the 26S proteasome. Molecular Cell. 2007 Apr 27;26(2):175-88. 
Start Year 2006
 
Description Professor Alfred Goldberg 
Organisation Harvard University
Department Harvard Medical School
Country United States 
Sector Academic/University 
PI Contribution Intellectual contribution and reagents
Collaborator Contribution Intellectual contribution and reagents
Impact Co-author of published paper in EMBO Journal, 2011 (Misfolded PrP impairs the UPS by interaction with the 20S proteasome and inhibition of substrate entry).
Start Year 2007
 
Description Professor Giampietro Schiavo 
Organisation Cancer Research UK
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Intellectual contribution and reagents.
Collaborator Contribution Intellectual contribution and reagents.
Impact Co-author of paper in Nature Communications, published in 2011 Goold R, Rabbanian S, Sutton L, Andre R, Arora P, Moonga J, Clarke AR, Schiavo G, Jat P, Collinge J, Tabrizi SJ. Rapid cell-surface prion protein conversion revealed using a novel cell system. Nature Communications. 2011;2:281. Goold R, McKinnon C, Rabbanian S, Collinge J, Schiavo G, Tabrizi SJ. Alternative fates of newly formed PrPSc upon prion conversion on the plasma membrane. Journal of Cell Science. 2013 Aug 15; 126(Pt 16):3552-62.
Start Year 2007
 
Description Professor Gillian Bates 
Organisation King's College London
Department School of Medicine KCL
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual Contribution and Reagents. Running in vivo aspects of the project.
Collaborator Contribution I was co-applicant on this grant. As well as funding there was intellectual contribution and reagents
Impact Gill Bates - she has been collaborating with Gill Bates since 2000 and is co-applicant on another MRC grant with Gill Bates: 3 papers from 2006 are: Tsang T, Woodman B, McGloughlin G, Griffin J, Tabrizi SJ, Bates GP, Holmes E. Metabanomic Characterisation of the R6/2 Transgenic Mouse Model of Huntington's Disease by High-Resolution MAS 1H NMR spectroscopy. Journal of Proteome Research. 2006 Mar;5(3):483-92. Alexandra Zourlidou, Tali Gidalevitz , Mark Kristiansen , Ben Woodman, Dominic J. Wells, David S. Latchman, Jackie de Belleroche, S. J. Tabrizi, Richard I. Morimoto and Gillian P. Bates. Hsp27 overexpression in the R6/2 mouse model of Huntington's Disease: Chronic Neurodegeneration does not Induce Hsp27 Activation. Human Molecular Genetics. Epub 2007 Mar 14. 2007 May 1;16(9):1078-90. Annette Dalrymple, Edward J Wild, Richard Joubert, Kirupa Sathasivam, Maria Björkqvist, Åsa Petersén, Jeremy Isaacs, Mark Kristiansen, Gillian P Bates Blair R Leavitt, Geoff Keir, Malcolm Ward, S. J Tabrizi. Proteomic profiling of plasma in Huntington's disease reveals neuroinflammatory activation and candidate biomarkers Journal of Proteome Research. 2007 Jul;6(7):2833-40. 2008 -2011 Identification and Cross-validation of Early Stage Phenotypes in Mouse Models of Huntington's disease. Ref G0800846 - MRC - Models of Disease grant. Co-applicant with Professor Gillian Bates (PI) and Dr Michael Modeo (co-applicant). £910,736
Start Year 2008
 
Description Professor Michael Glickman 
Organisation Technion - Israel Institute of Technology
Department Faculty of Biology
Country Israel 
Sector Academic/University 
PI Contribution Intellectual contribution and reagents
Collaborator Contribution Intellectual contribution and reagents.
Impact Co-author of paper in EMBO Journal 2011 (Misfolded PrP impairs the UPS by interaction with the 20S proteasome and inhibition substrate entry).
Start Year 2007
 
Description 25th International Symposium on ALS/MND, Brussels 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Presented educational talk on HD to MNDA members
Year(s) Of Engagement Activity 2014
 
Description Article in The Economist 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact My work was summarised in an article in The Economist(http://www.economist.com/science/displaystory.cfm?story_id=9794864).

The article was picked up by national newspapers.
Year(s) Of Engagement Activity 2007
 
Description Brains Talk Seminar at Roche 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Presented seminar on Hutington's Disease to Roche Pharmaceuticals to aid company strategic planning
Year(s) Of Engagement Activity 2015
 
Description CAG Triplet Repeat Disorders, Tuscany, Italy 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Presented talk on HD research to scientific peers and healthcare professionals
Year(s) Of Engagement Activity 2015
 
Description CHDI 10th Annual HD Therapeutics Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Presented talk on HD studies to researchers, healthcare practitioners and students.
Year(s) Of Engagement Activity 2015
 
Description Dendron Annual Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Health professionals
Results and Impact Presenting information regarding the TRACK-HD Clinical Study

The organisers received positive feedback from participants from all over the world
Year(s) Of Engagement Activity 2008,2009,2010,2011
 
Description HD Website 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Articles of this nature serve to enhance engagement with my research

Positive feedback from patients and healthcare professionals
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016
 
Description Interview/profile in Lancet Neurology 
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 Other audiences
Results and Impact Professor Sarah Tabrizi completed a profile interview in the Lancet Neurology. Helps raise the profile of her research and the UCL HD Centre.
Year(s) Of Engagement Activity 2017
URL http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(17)30303-4/abstract
 
Description Key Advances in Neurodegenerative Disorders Meeting, Royal Society of Medicine 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presented education talk on HD to healthcare professionals
Year(s) Of Engagement Activity 2014
 
Description MRC Centre for Neuromuscular Diseases Seminar Series 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Presented talk on therapeutic strategies in HD to students and professional practitioners alike. The talk generated lot's of interest and questions.
Year(s) Of Engagement Activity 2015