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MRC Prion Unit
From fundamental research to prevention and cure
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Overview

Prion Strain Mutation and Selection
Prion Strain Mutation and Selection

Prions have attracted immense research interest for many years because of their unique composition and properties - being apparently devoid of significant nucleic acid (genes). According to the widely accepted ‘protein-only’ hypothesis, an abnormal form of one of the body’s own proteins, the cellular prion protein (PrPC) is converted to an alternative form designated PrPSc. It is proposed that PrPSc acts as a template which promotes the conversion of PrPC to PrPSc and that the difference between these isoforms lies purely in conformation (shape) and its state of aggregation.

In addition to ongoing public health concerns, prions have assumed much wider relevance in understanding neurodegenerative and other diseases involving accumulation of misfolded host proteins (“protein-folding diseases”) and analogous processes are described in yeast and fungi involving distinct proteins with prion-like properties. Central to understanding prion propagation remains the conundrum of prion strains - how a protein-only infectious agent can encode information required to specify distinct disease patterns – and also the so-called species barrier effect which limits cross species infection. While considered different aspects of the prion problem it is now clear that species barriers and strains are intimately related by a mechanism we defined as “conformational selection”.

The principles of protein conformation-based inheritance that emerged from study of mammalian prions are now strongly supported by elegant studies with analogous systems in yeast models. While at least some yeast and fungal prions may, in certain environments, confer advantage to their hosts, mammalian prions cause massive cell death in the central nervous system. The basis of this profound neurotoxicity has been poorly understood and, intriguingly, it appears to relate neither to loss of the normal function of PrPC nor to direct toxicity of PrPSc. Understanding these interlinked phenomena will not only facilitate development of diagnostics and therapeutics but will also illuminate processes involving protein misfolding and aggregation, and protein-based inheritance, which clearly have far-reaching implications in disease biology, ageing and the evolution of cellular processes.

We have recently summarised the Unit’s thinking on prion strains and neurotoxicity, and proposed a general model of prion propagation in the academic journal Science which also outlines the wider relevance of these emerging concepts in neurodegeneration. Some features of Alzheimer pathology can also be transmitted to laboratory animals in an appropriate experimental situation. Prion-like seeded aggregation processes may be fundamental in understanding what triggers disease onset in other degenerative brain diseases, how the protein-aggregation process spreads in the brain, and how toxic species are generated in this process. In this regard, prion disease not only provides the archetypal paradigm, but also supplies a body of experience and specialised techniques. Not least these include animal models which are without parallel in terms of their faithful recapitulation of human pathology.

Owing to our fundamental understanding of prion diseases, there is a real possibility that they will be the first neurodegenerative disorders for which curative treatments become available. Such studies may provide a key paradigm for studying the pathways of late onset neurodegeneration and the ability of the brain to recover function following therapeutic intervention: much will be learnt of far wider relevance in neurodegenerative disease.

The aims of the Unit remain the achievement of a comprehensive understanding of the molecular basis of prion propagation, strain diversity and neurotoxicity with effective translation to public health and clinical care. We aim to develop and validate early diagnosis of, and curative treatment for, prion infection. The Unit has now developed highly multidisciplinary, closely integrated and interdependent teams spanning basic molecular biology, through cellular and animal models to clinical research and has a proven national clinical trials capability in a neurological disease. This experience is allied with superb external collaborators and industrial colleagues to translate basic research to patient care.

MRC Prion News