Protein misfolding in neurodegenerative disease
Lead Research Organisation:
University of Edinburgh
Department Name: The Roslin Institute
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
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.
Planned Impact
unavailable
People |
ORCID iD |
| Jean Manson (Principal Investigator) |
Publications
Campbell L
(2013)
The PrP(C) C1 fragment derived from the ovine A136R154R171PRNP allele is highly abundant in sheep brain and inhibits fibrillisation of full-length PrP(C) protein in vitro.
in Biochimica et biophysica acta
Graham JF
(2010)
Low density subcellular fractions enhance disease-specific prion protein misfolding.
in The Journal of biological chemistry
Jeffrey M
(2015)
Membrane pathology and microglial activation of mice expressing membrane anchored or membrane released forms of Aß and mutated human Alzheimer's precursor protein (APP).
in Neuropathology and applied neurobiology
Jeffrey M
(2012)
Mechanism of PrP-amyloid formation in mice without transmissible spongiform encephalopathy.
in Brain pathology (Zurich, Switzerland)
Jones M
(2009)
Molecular model of prion transmission to humans.
in Emerging infectious diseases
Kirby L
(2010)
Inverse correlation of thermal lability and conversion efficiency for five prion protein polymorphic variants.
in Biochemistry
Piccardo P
(2013)
Dissociation of prion protein amyloid seeding from transmission of a spongiform encephalopathy.
in Journal of virology
Ritchie M
(2013)
Lysine hydroxylation and O-glycosylation in the globular, C-terminal region of mammalian-expressed, recombinant PrP
in International Journal of Mass Spectrometry
Sanghera N
(2011)
Deciphering the Molecular Details for the Binding of the Prion Protein to Main Ganglioside GM1 of Neuronal Membranes
in Chemistry & Biology
Tan BC
(2012)
Significant differences in incubation times in sheep infected with bovine spongiform encephalopathy result from variation at codon 141 in the PRNP gene.
in The Journal of general virology
Young D
(2009)
Effect of enzymatic deimination on the conformation of recombinant prion protein
in Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
| 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 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 | 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 |