Protein misfolding in neurodegenerative disease

Lead Research Organisation: University of Edinburgh
Department Name: The Roslin Institute

Abstract

We aim to investigate the mechanisms of protein misfolding that lead to neurodegenerative disorders, including defining how, why and when it may occur in vivo. The study of well defined model systems such as the TSEs are expected to identify mechanisms which will be common to other protein misfolding diseases. The objectives of this theme are: To define the detailed molecular mechanisms underpinning protein misfolding. To define the roles of amino acid changes in protein misfolding. To define the contribution of post-translational modifications to the misfolding process. To define the roles of misfolded isoforms of protein in the pathobiology of disease.

Publications

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Graham JF (2010) Low density subcellular fractions enhance disease-specific prion protein misfolding. in The Journal of biological chemistry

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Jones M (2009) Molecular model of prion transmission to humans. in Emerging infectious diseases

 
Description We have identified post-translational modifications which can impact on prion protein misfolding. The amino acid at codon 141 of ovine PrP was shown to be a key determinant of susceptibility to acquired prion disease.
The analysis of natural occurring ovine PrP protein variants for biochemical characteristics showed how they may modulate prion replication Our studies have shown that the level of proteolytic processing of ovine PrPC is associated with PRNP genotype and that fibrillisation of full-length PrPC can be inhibited by smaller PrPC fragments.
Transgenic mice overexpressing mutant 101L PrP were shown to form PrP amyloid plaques in the brain during aging, but did not develop clinical signs of TSE. Thus we have demonstrated PrP amyloid plaques can be seeded in the absence of agent replication, and misfolded/aggregated PrP is therefore not necessarily infectious or neurotoxic.
Exploitation Route through further research
Sectors Agriculture, Food and Drink

 
Description Member of the ACDP
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact The Advisory Committee on Dangerous pathogens advises the UK government on all issues related to dangerous pathogens from situations, in the field, in health care and laboratory practice. I serve on the committee as the expert on the Transmissible Spongiform Encephalopathies
 
Description Member of the British Neuroscience Advisory Board
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Member of the CJD Sample Oversight Committee Group
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact The committee aims to facilitate the development of diagnostics for vCJD through working with developers and providing access to rare samples
 
Description Member of the European Food Safety Authority
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact involved in development of policy on prion diseases
 
Description Member of the International Science Advisory Council of APRI
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact The importance of this committee which I now chair is to provide scientific knowledge and expertise to the growing scientific community of the APRI
 
Description Member of the UK SEAC Advisory Body
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact Spongiform Encephalopathy Advisory Committee advised Government on all accept of the Transmissible Spongiform Encephalopathies throughout the BSE and vCJD epidemics
 
Description WHO TSE Working Group
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact developed policy on prion diseases
 
Description QuIC analysis of low PrPSc mouse models 
Organisation National Institute of Allergy and Infectious Diseases (NIAID)
Department Rocky Mountain Laboratories
Country United States 
Sector Public 
PI Contribution Provision of brain tissue from an unique mouse model of TSE disease
Collaborator Contribution Performed QuIC analysis of material from our mouse model
Impact Vascellari S, Orrù CD, Hughson AG, King D, Barron RM, Wilham JM, Baron GS, Race B, Pani A and Caughey B (2012). Prion seeding activities of mouse scrapie strains with divergent PrPSc protease sensitivities and amyloid plaque content using RT-QuIC and eQuIC. PLoS One 7:e48969
 
Description Seeding protein aggregation in mice 
Organisation Colorado State University
Country United States 
Sector Academic/University 
PI Contribution Analysis of amyloid plaque seeding in mouse brain
Collaborator Contribution Provision of mice and tissue from animals overexpressing 101L PrP
Impact Piccardo P, King D, Telling G, Manson JC and Barron RM (2013). Dissociation of prion protein amyloid seeding from transmission of a spongiform encephalopathy. J Virol. 87:12349-12356 doi: 10.1128/JVI.00673-13
 
Description BNA Streetfair 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact British Neuroscience Association Streetfair, held at the Barbican Centre in London alongside the annual BNA symposium. Activity to communicate work we do on TSE disease, protein misfolding and neurodegeneration to the public
Year(s) Of Engagement Activity 2013
 
Description Prion 2016 chair and invited speaker 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact invited talk to international meeting
Year(s) Of Engagement Activity 2016
 
Description Roslin Institute Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Each year we run an activity designed to engage the public and introduce them to the work we do on TSE diseases, protein misfolding and neurodegeneration
Year(s) Of Engagement Activity 2012,2013,2014,2015,2016