Principal Investigators


Professor J Collinge

Institution


MRC Prion Unit

Contact information of lead PI


Country


United Kingdom

Title of project or programme


Prion kinetics, toxicity and synthesis and its wider relevance

Source of funding information


MRC

Total sum awarded (Euro)


€ 12,738,256

Start date of award


01/04/2008

Total duration of award in years


5.0

The project/programme is most relevant to:


Prion disease

Keywords


Prion| neurodegeneration| protein misfolding| Alzheimer| neurotoxicity| bioassay| cell culture| animal models| therapeutics

Research Abstract


Prions are lethal pathogens of mammals which occur in multiple biological strains, and yet appear devoid of nucleic acid and composed of aggregated conformational isomers of a host-encoded glycoprotein. Their unique Biology, allied with the risks to public health posed by prion zoonoses such as BSE, has focused much attention on understanding the molecular basis of prion propagation and pathogenesis. However, it is clear that the underlying molecular mechanisms, involving aggregation of a misfolded host protein, are of much wider significance and, indeed, analogous protein-based inheritance mechanisms are recognised in yeast and fungi. The common neurodegenerative diseases also involve accumulation of misfolded host proteins and parallels, at multiple levels, in particular with Alzheimers disease, are becoming increasingly apparent. Recent advances suggest that prions themselves are not directly neurotoxic, but rather their propagation involves production of toxic species which may be uncoupled from infectivity. We have proposed a general model to encompass these phenomena, centring on the kinetics of prion propagation, and will test this model using various experimental systems. Our development of an automated, high-throughput, culture-based prion bioassay (ASCA) will be applied to study in vivo kinetics of prion propagation in multiple models and relate this to neurotoxicity and clinical onset. We aim to specifically characterise the determinants of chronic carrier states of prion infection. ASCA will also be used in large-scale studies to attempt high-titre prion synthesis from purified components, an approach completely impractical by conventional rodent bioassay, and determine the role of co-factors. The hypothesis that prion neurotoxicity is mediated by oligomeric species will also be directly investigated. We also aim to develop cell lines to efficiently propagate hamster and human prions to allow extension of these studies beyond mouse-adapted scrape strains and to provide rapid assay of vCJD prions. Interactions between prion and Alzheimer pathogenesis will be explored at several levels, and we will investigate the possible wider role of PrPC in neurotoxicity. Molecular reagents we have developed to target PrPC will be used to investigate possible wider therapeutic strategies in neurodegeneration. Our prion models also provide a test bed for investigating generic approaches to protein misfolding diseases.

Lay Summary


Prions are germs that cause fatal brain diseases like CJD in humans and BSE (mad cow disease) in cattle. Unlike bacteria or viruses they do not carry their own genes but are made up of rogue forms of one of our own proteins, which build up in the brain as clumps. This unique Biology, together with risks to public health from BSE and other prion diseases, has focused our attention on understanding how prions multiply and cause damage to brain cells. We think it is not the prions themselves that damage the brain, but rather something else that is produced when prions grow and have proposed a theory which tries to bring together and explain all we know about prions; we are now testing this to see if it holds up. To do this we have developed a new way of measuring prions. This has been done in the past by injecting material into mice. Our new method just uses mouse cells and so completely avoids having to do animal experiments. We have automated the test and it is much quicker, cheaper and more accurate than using mice. We are developing new cells to measure human prions. It is now clear that what we have been studying in prion diseases is of much wider significance as the commoner dementias like Alzheimers also involve build up of rogue proteins and similar mechanisms may be involved. We will study interactions between prion and Alzheimer disease and see if treatments we are developing for CJD might also work in Alzheimers and other diseases.

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