Prion diseases or TSEs
Prion diseases, also called TSEs (Transmissible Spongiform Encephalopathies), constitute a biological enigma and the sole example of a transmissible disease whose origin is still unknown.
Several landmark studies have advanced our understanding of prion diseases :
- First, the demonstation by two French' veterinarians (Paul-Louis Chelle and Jean Cuillé) in 1936 that scrapie was transmissible by inoculation of affected sheep central nervous tissue from affected to healthy sheep,
- Second, the demonstration by D. Carleton Gajdusek (Nobel Prize in 1976) that both kuru (linked to cannibalism in highland peoples of New-Guinea) and Creutzfeldt-Jakob disease were transmissible by inoculation of brain tissue from affected humans into chimpanzees and monkeys,
- Third, the demonstration by Stanley B. Prusiner (Nobel Prize in 1997) and his collaborators that a host-encoded protein, named prion protein, or PrP, accumulates in the brain of affected animals and humans in an abnormal form and is closely associated with (and possibly the sole cause of) infectivity.
The causal agents of TSEs have been successively called unconventional transmissible agents, unconventional slow viruses, virinos and TSE agents or prions. These agents multiply in the lymphoid tissues (lymph nodes, spleen, tonsils, appendix...) and especially in the central nervous system (brain and spinal cord).
No effective treatment has yet been developed, and the clinical course is unremittingly fatal.
Prions: neither viruses nor bacteria, a new form of infectious agents
The exact nature of the TSE agents is not yet completely elucidated and various hypotheses have been postulated, including that of the prion. This last hypothesis that the infectious agent is a protein was at the opposite of the current knowledge on infectious agents (in which the genetic information relies on nucleic acids) and has been highly debated in the scientific community.
In 1966, a biologist in London, Tikvah Alper, discovered that ultraviolet radiation, which destroys nucleic acids, the most basic forms of life, including viruses, has no effect on the agent responsible for scrapie. The infectious agent therefore seems not to contain nucleic acid (DNA or RNA), and so may be a protein.
The following year, again in London, a mathematician, John S. Griffith, reported that his modelling suggested that the infectious agent of scrapie is a protein whose three-dimensional structure is altered and which multiplies by self-association.
In 1970, Raymond Latarget of the Institute of Radium (now the Institute Curie) in France confirmed by means of inactivation tests the apparently purely proteic nature of this strange infectious cellular agent.
Numerous resarch groups observed the abnormally high resistance of TSE agents to decontamination in different models : scrapie in sheep and mice (notably the team of A. Dickinson in Edinbourgh, UK), Kuru and Creutzfeldt-Jakob disease in primates (the group of DC Gajdusek and CJ Gibbs in US).
The Californian neurobiologist Stanley Prusiner reviewed all these data and demonstrated that these TSE agents, which are insensitive to physical agents (heat, ionizing radiation ... ) and chemicals (strong mineral acids, aldehydes like formol), in practice resist all the processes that degrade nucleic acids, whereas they are sensitive to those which destroy proteins. Since this fundamental work (1982), Prusiner has defended the hypothesis that the infectious agent of TSEs is an infectious protein, for which he coined the term 'prion' from 'PROteinaceous INfectious particle'.
It is commonly admitted that proteins do not carry genetic information, but rather result from its expression. Because of this, Prusiner in his initial hypothesis proposed that the pathogenic prion is a protein foreign to the host which commandeers the host's cellular machinery in order to multiply. As was to be expected, this highly provocative hypothesis was greeted with great scepticism by microbiologists, although they were unable to demonstrate its inexactitude.
In 1984, a protein found in semi-purified brain extracts from hamsters infected by an experimental strain of scrapie was partially purified and baptised 'prion protein', and then sequenced (i.e. the order, or sequence, of its amino acids was determined). This short sequence enabled the construction of nucleic probes and the search for the gene responsible for the synthesis of this prion protein. To everyone's surprise, two teams (Charles Weismann's in Switzerland and Bruce Chesebro's in the United States) rapidly identified in 1985 a genetic sequence corresponding to a cellular protein: this normal cellular prion protein (PrPc) is localized at the surface of healthy nerve cells. In sick animals, this protein exists in its normal form, PrPc, which is present in all healthy animals, and in an abnormal, pathological form, called PrPsc (for scrapie) or PrPres (for resistant), which is not degraded by proteases (enzymes that destroy proteins) and which therefore accumulates in the brain, leading to spongiform encephalopathy. Far from rejecting the prion hypothesis, this approach redirected it. The concept of a protein foreign to the host was thus replaced by a model based on the transformation of the normal structure of the prion protein, itself naturally synthesized in the neurones.
The two forms of PrP differ only by a change in conformation, that is by a difference in three-dimensional structure. This structural change greatly alters their respective properties. Thus, PrPc is soluble in water whereas PrPres is insoluble, even in the presence of detergents known to solubilize many products. Unlike conventional proteins (albumin, for example), the particular structure of PrPres confers on it exceptional resistance to the most of the methods generally used to destroy these macromolecules: heat treatments, chemical and enzymatic treatments. This allows prions to be differentiated from conventional infectious agents, like bacteria and viruses. During the incubation period (pre-clinical phase) of prion diseases, PrPres usually accumulates in the zones of the brain which will later show histological lesions responsible for the clinical features. Most of the scientific community considers the accumulation of the abnormal PrP (PrPres) as responsible for the destruction of the nervous system during these diseases.
Today the accumulated evidence has persuaded most scientists that the 'protein-only' hypothesis is probably correct, although there remain a few uncertain issues, and formal proof is still lacking. To avoid any semantic confusion, it is wise to distinguish the prion protein (the normal protein present in all mammals) from 'prions', which have come to be considered the infectious agents responsible for TSEs.