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Sunday, 30 March 2003 05:30 PM GMT
Knowledge begins with a hypothesis or theory that should be subjected to and verified by experimentation. In this article we will highlight on one of these hypothesis that was for a long time not credible and almost not palatable to many.
The protein only hypothesis or prions hypothesis is a novel discovery that earned the scientist Stanley Ben Prusiner the Nobel prize for medicine in 1997. Prion diseases are a group of diseases that share common clinical and neuropathological characteristics. They are also called spongiform encephalopathies because of the post mortem appearance of the brain with large vacuoles in the cortex and cerebellum a change that is caused by prion protein. Worth noting that 2 nobel prizes were given for research related to this scientific field.
In 1920, Hans Gerhard Creutzfeldt described the first case of a progressive
mental and neurological disturbance in a 23 year old woman. Alfons Maria
Jakob described another three cases of defects in the motor systems one
year later. In 1922 the eponym 'Creutzfeldt-Jakob disease' (CJD) was first
used to describe a number of degenerative central nervous system diseases
In 1950s, a peculiar disease known as 'kuru', in the Eastern Highlands of Papua New Guinea has been discovered and turned out to be due ingesting brain tissue of dead relatives for religious reasons. The neuroplathological similarity between kuru, CJD, and scrapie (which is a disease affecting sheeps discovered 1973 with higher incidence in the UK) was discovered (3-6).
In 1960s, the term transmissible spongiform encephalopathy was applied after the discovery of the transmissible ability of both kuru and CJD diseases to chimpanzees (5, 7).
For years it was thought that the disease is caused by 'slow' or 'unconventional' viruses causing amyloidoses of the nervous system. In 1976 Daniel Carleton Gajdusek was awarded the first Nobel prize for his work on 'slow virus' infections theory (8).
1980s the term 'prion' was used to designate a small proteinaceous infectious particle that was resistant to inactivation by most of the procedures that modify nucleic acids, and to distinguish the agent from virus and viroids. These protein particles are the causative infectious agents for the prion diseases. This theory, also known as the 'protein-only' hypothesis and has been under criticism for years (5).
Routes of infection
The proved routes of infections are:
1. Acquired infection (diet and following medical procedures such as surgery, growth hormone injections, corneal transplants) i.e. an infectious agent is implicated. Prions are 'sticky' proteins that tend to aggregate. Being resistant to heat and to digestive enzymes they can reach the circulation after oral ingestion of infected animal meat products (9-11).
2. Apparent hereditary (an autosomal and dominant trait) 10-15%. The human PrP-gene (PRNP), which encodes the 253-amino acid prion protein, is localized on the short arm of chromosome 20. Studies have shown a strong, but not absolute, correlation between specific PRNP mutations and different clinical forms of familial prion diseases (1-3, 8, 12).
Post-mortem examination reveals non-inflammatory lesions, vacuoles, amyloid protein deposits and astrogliosis
Biochemical and genetic explanations for the prion theory (13):
This protein can adopt 2 quite different stable conformational forms. The safe PrPc form (normal celleular protein) which can, although rarely, transform to the PrPsc form (scrapie). PrPsc is a protease resistant form of PrPc that accumulates in cytoplasmic vesicles of diseased individuals leading to amyloid changes and giosis.
No chemical differences between the two forms of the protein have been detected. However, the conformational 3D structure using spectroscopy measurements revealed a structural change between the two proteins.
Mutations of PrP- gene are also thought to favor the switch of PrPc into PrPsc, it enhances the rate of spontaneous conversion of PrPc to PrPsc which permits disease manifestation within the lifetime of an individual.
Animal diseases (13-15): are mainly
- Scrapie affecting mainly sheep rarely goats.
- Transmissible mink encephalopathy (TME) affecting minks.
- Chronic wasting disease (CWD) of mule-deer, elk
- Bovine spongiform encephalopathy (BSE or 'mad cow disease'). Which occurred in outbreak in mid 1980 followed by outbreak of special type of CJD (varient CJD) in the UK and to lesser extent other European countries.
In humans are mainly (16-20):
- Creutzfeldt-Jakob disease (sCJD).
- New variant form of CJD (vCJD)
- Gerstmann-Str?ssler-Scheinker disease (GSS)
- Fatal insomnia
Clinical picture (13, 20, 21)
The diseases are characterised by loss of motor control, progressive
dementia, paralysis and wasting. In the terminal stage, the patient is usually
mute, rigid and unresponsive (akinetic mutism) with decorticated or decerebrate
posture as well as fecal and urinary incontinence.
CJD typically occurs a decade later, has cerebral involvement so dementia is more common and patient seldom survives a year .
GSS is distinct from CJD, it occurs typically in the 4th-5th decade, characterised by cerebellar ataxia and concomitant motor problems, dementia is less common and disease course lasts several years before ultimate death.
Fatal insomnias present with an untreatable insomnia and dysautonomia. Pathological changes are characterized by severe selective atrophy of the thalamus.
Alpers syndrome is the name given to prion diseases in infants.
Prognosis: death within one year after the onset of symptoms in 90%, and a further 5% of patients die within the next year.
Anti-prion drugs are being developed.
Researchers focus on agents which reduce PrP expression. Similarly agents destabilising the PrPsc conformation may be effective. In this regard several vaccines to Alzheimers amyloid plaques are in clinical trials (both diseases show similarity in the pathological changes).
Agents which interfere with PrPc-PrPsc interaction may be effective.
A number of reagents showing affinity for amyloid proteins are known e.g congo red and is being studied.
Chemicals affecting the endocytosis, exocytosis, intracellular trafficking and degradation of proteins and in particular PrP aiming to decrease expression level of the prions in the cells. Amphotericin for instance is reported to delay prion disease in hamsters (although it apparently has little effect in humans). Also, a trial of quinacrine, an anti-malarial, and chlorpromazine, an anti-psychotic was done.
Very recently a successful trial of injecting antibodies that latch onto prions into mice that that were 30 days into the disease - before symptoms occur, but at a time when prions are multiplying ferociously. The animals stayed healthy for at least two years, rather than dying by the time they reached seven months (22).
Scientists are now concerned about processing this antibody and hope for wining the battle against this disease in humans. An achievement that might give scientists the 3rd Nobel prize in the same disease.
1- Prusiner SB. Genetic and infectious prion diseases. Arch Neurol 1993;50:1129-1153.
2- Collinge J. Inherited prion diseases. In: Harding AE, Deufel T, editors. Advances in Neurology. New York: Raven Press Ltd., 1993;61:155-165.
3- Kretzschmar HA. Neuropathology of human prion diseases (spongiform encephalopathies). In: Brown F, editor. Transmissible spongiform encephalopathies - Impact on animal and human health. Dev Biol Stand: Basel, Karger, 1993;80:71-90
4- Kretzschmar HA. Human prion diseases (spongiform encephalopathies). Arch Virol (Suppl) 1993;7:261-293.
5- Prusiner SB. Prions. Sci Am 1984;October:48-57.
6- Gajdusek DC, Zigas V. Clinical, pathological and epidemiological study of an acute progressive degenerative disease of the central nervous system among natives of the Eastern Highlands of New Guinea. Am J Med 1959;26:442-469.
7- Ravilochan K, Tyler KL. Human transmissible neurodegenerative diseases (prion diseases). Semin Neurol 1992;12:178-192.
8- Prusiner SB, Hsiao KK, Bredesen DE, DeArmond SJ. Prion disease. In: Vinken PJ, Bruyn GW, Klawans HL, editors Handbook of Clinical Neurology. Amsterdam, the Netherlands: Elsevier Science Publishers, 1989;543-580.
9- Liberski PP. The enigma of slow viruses. Facts and artefacts. Arch Virol (Suppl) 1993;6:1-263.
10- Bradley R. Animal prion diseases. In: Collinge J, Palmer MS, editors. Prion Diseases. Oxford University Press; 1997, 91-129.
11- Collee JG. A dreadful challenge. Lancet 1996;347:917-918.
12- Dal Canto MC. Human and experimental spongiform encephalopathies: recent progress in pathogenesis. Ital J Neurol Sci 1991;12:147-153.
13- S. Jane Flint (Editor) et al .Prion disease. Molecular Biology, Pathogenesis, and Control. Principles of molecular virology.1999 ;8-258.
14- Schreuder BEC. Animal spongiform encephalopathy - an update. Part 1. Scrapie and lesser known animal spongiform encephalopathies. Vet Q 1994;16:174-181.
15- Nathanson N, Wilesmith J, Wells GA, Griot C. Bovine spongiform encephalopathy and related diseases. In: Prusiner SB, editor Prion Biology and Diseases. Cold Spring Harbor Laboratory Press, 1999.
16- Gajdusek DC. Unconventional viruses and the origin and disappearance of kuru. Science 1977;197:943-960.
17- Will RG, Alpers MP, Dormont D, Schonberger LB, Tateishi J. Infectious and sporadic prionprotein disease In: Prusiner SB, editor. Prion Biology and Diseases. Cold Spring Harbor Laboratory Press, 1999.
18- Gambetti P, Petersen RB, Parchi P, Chen SG, Capellari S, Goldfarb L, et al. Inherited prion diseases. In: Prusiner SB, editor. Prion Biology and Diseases. Cold Spring Harbor Laboratory Press, 1999.
19- Mastrianni JA, Nixon R, Layzer R, Telling GC, Han D, DeArmond SJ, Prusiner SB. Prion protein conformation in a patient with sporadic fatal insomnia. NEJM 1999;340:1630-1638.
20- Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, et al.
Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999;46:224-233.
21- Prusiner SB. Human prion diseases. In: Zuckerman AJ, Pattison JR, Banatvala JE, editors. Principles and Practice of Clinical Virology. 3rd ed. Chichester, England: John Wiley & Sons, 1994;703-729.
22- White, A. R. et al. Monoclonal antibodies inhibit prion replication and delay the development of prion disease. Nature, 422, 80 - 83, (2003).
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