Transmissible spongiform encephalopathy

Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are a group of progressive conditions that affect the brain (encephalopathies) and nervous system of many animals, including humans. According to the most widespread hypothesis, they are transmitted by prions, though some other data suggest an involvement of a Spiroplasma infection.^[1] Mental and physical abilities deteriorate and myriad tiny holes appear in the cortex causing it to appear like a sponge (hence spongiform) when brain tissue obtained at autopsy is examined under a microscope. The disorders cause impairment of brain function, including memory changes, personality changes and problems with movement that worsen over time. Prion diseases of humans include classic Creutzfeldt–Jakob disease, new variant Creutzfeldt–Jakob disease (nvCJD, a human disorder related to bovine spongiform encephalopathy), Gerstmann–Sträussler–Scheinker syndrome, fatal familial insomnia, kuru, and the recently discovered variably protease-sensitive prionopathy. These conditions form a spectrum of diseases with overlapping signs and symptoms.

Unlike other kinds of infectious disease, which are spread by microbes, the infectious agent in TSEs is believed to be a type of protein, called the prion protein. Misshapen prion proteins carry the disease between individuals and cause deterioration of the brain. TSEs are unique diseases in that their aetiology may be genetic, sporadic, or infectious via ingestion of infected foodstuffs and via iatrogenic means (e.g., blood transfusion).^[2] Most TSEs are sporadic and occur in an animal with no prion protein mutation. Inherited TSE occurs in animals carrying a rare mutant prion allele, which expresses prion proteins that contort by themselves into the disease-causing conformation. Transmission occurs when healthy animals consume tainted tissues from others with the disease. In recent times, a type of TSE called bovine spongiform encephalopathy (BSE) spread in cattle in an epidemic fashion. This occurred because cattle were fed the processed remains of other cattle, a practice now banned in many countries.

Prions cannot be transmitted through the air or through touching or most other forms of casual contact. However, they may be transmitted through contact with infected tissue, body fluids, or contaminated medical instruments. Normal sterilization procedures such as boiling or irradiating materials fail to render prions non-infective.

Classification

History

In the 5th century BCE, Hippocrates described a disease like TSE in cattle and sheep, which he believed also occurred in man.^[4] Publius Flavius Vegetius Renatus records cases of a disease with similar characteristics in the 4th and 5th centuries AD.^[5] In 1755, an outbreak of scrapie was discussed in the British House of Commons and may have been present in Britain for some time before that.^[6] Although there were unsupported claims in 1759 that the disease was contagious, in general it was thought to be due to inbreeding and countermeasures appeared to be successful. Early-20th-century experiments failed to show transmission of scrapie between animals, until extraordinary measures were taken such as the intra-ocular injection of infected nervous tissue. No direct link between scrapie and disease in man was suspected then or has been found since. TSE was first described in man by Alfons Maria Jakob in the 1921.^[7] Daniel Carleton Gajdusek's discovery that Kuru was transmitted by cannibalism accompanied by the finding of scrapie-like lesions in the brains of Kuru victims strongly suggested an infectious basis to TSE.^[8] The priority given the search for a viral infectious agent almost cost Stanley Prusiner tenure when his research showed that a protein transferred the disease.^[9] A paradigm shift to a non-nucleic infectious entity was required when the results were validated with an explanation of how a prion protein might transmit spongiform encephalopathy.^[10] It wasn't until 1988 that the neuropathology of spongiform encephalopathy was properly described in cows.^[11] The alarming amplification of BSE in the British cattle herd heightened fear of transmission to humans and reinforced the belief in the infectious nature of TSE. This was confirmed with the identification of a Kuru-like disease, called new variant Creutzfeldt–Jakob disease, in humans exposed to BSE.^[12] Although the infectious disease model of TSE has been questioned in favour of a prion transplantation model that explains why cannibalism favours transmission,^[13] the search for a viral agent is being continued in some laboratories.^[14]

Features of TSE

The degenerative tissue damage caused by human prion diseases (CJD, GSS, and kuru) is characterised by four features: spongiform change, neuronal loss, astrocytosis, and amyloid plaque formation. These features are shared with prion diseases in animals, and the recognition of these similarities prompted the first attempts to transmit a human prion disease (kuru) to a primate in 1966, followed by CJD in 1968 and GSS in 1981. These neuropathological features have formed the basis of the histological diagnosis of human prion diseases for many years, although it was recognized that these changes are enormously variable both from case to case and within the central nervous system in individual cases.^[15]

The clinical signs in humans vary, but commonly include personality changes, psychiatric problems such as depression, lack of coordination, and/or an unsteady gait (ataxia). Patients also may experience involuntary jerking movements called myoclonus, unusual sensations, insomnia, confusion, or memory problems. In the later stages of the disease, patients have severe mental impairment (dementia) and lose the ability to move or speak.^[16]

Early neuropathological reports on human prion diseases suffered from a confusion of nomenclature, in which the significance of the diagnostic feature of spongiform change was occasionally overlooked. The subsequent demonstration that human prion diseases were transmissible reinforced the importance of spongiform change as a diagnostic feature, reflected in the use of the term "spongiform encephalopathy" for this group of disorders.

Prions appear to be most infectious when in direct contact with affected tissues. For example, Creutzfeldt–Jakob disease has been transmitted to patients taking injections of growth hormone harvested from human pituitary glands, from cadaver dura allografts and from instruments used for brain surgery (Brown, 2000) (prions can survive the "autoclave" sterilization process used for most surgical instruments). It is also believed that dietary consumption of affected animals can cause prions to accumulate slowly, especially when cannibalism or similar practices allow the proteins to accumulate over more than one generation. An example is kuru, which reached epidemic proportions in the mid-20th century in the Fore people of Papua New Guinea, who used to consume their dead as a funerary ritual.^[17] Laws in developed countries now ban the use of rendered ruminant proteins in ruminant feed as a precaution against the spread of prion infection in cattle and other ruminants.

Note that not all encephalopathies are caused by prions, as in the cases of PML (caused by the JC virus), CADASIL (caused by abnormal NOTCH3 protein activity), and Krabbe disease (caused by a deficiency of the enzyme galactosylceramidase). Progressive Spongiform Leukoencephalopathy (PSL)—which is a spongiform encephalopathy—is also probably not caused by a prion, although the adulterant that causes it among heroin smokers has not yet been identified.^{[18][19][20][21]} This, combined with the highly variable nature of prion disease pathology, is why a prion disease cannot be diagnosed based solely on a patient's symptoms.

Genetics

Mutations in the PRNP gene cause prion disease. Familial forms of prion disease are caused by inherited mutations in the PRNP gene. Only a small percentage of all cases of prion disease run in families, however. Most cases of prion disease are sporadic, which means they occur in people without any known risk factors or gene mutations. In rare circumstances, prion diseases also can be transmitted by exposure to prion-contaminated tissues or other biological materials obtained from individuals with prion disease.

The PRNP gene provides the instructions to make a protein called the prion protein (PrP). Under normal circumstances, this protein may be involved in transporting copper into cells. It may also be involved in protecting brain cells and helping them communicate. 24 Point-Mutations in this gene cause cells to produce an abnormal form of the prion protein, known as PrP^Sc. This abnormal protein builds up in the brain and destroys nerve cells, resulting in the signs and symptoms of prion disease.

Familial forms of prion disease are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the altered gene from one affected parent.

In some people, familial forms of prion disease are caused by a new mutation in the PRNP gene. Although such people most likely do not have an affected parent, they can pass the genetic change to their children.

Competing hypotheses

Protein-only hypothesis

Protein could be the infectious agent, inducing its own replication by causing conformational change of normal cellular PrP^C into PrP^Sc. Evidence for this theory:

• infectivity titre correlates with PrP^Sc levels. However, this is disputed.^[22]
• PrP^Sc is an isomer of PrP^C
• Denaturing PrP removes infectivity^[23]

• PrP-null mice cannot be infected^[24]
• PrP^C knockout in mice following inoculation with PrP^Sc reverses early spongeosis and behavioural deficits, halts further disease progression and increases life-span ^[25]

Multi-component hypothesis

While not containing a nucleic acid genome, prions may be composed of more than just a protein. Purified PrP^C appears unable to convert to the infectious PrP^Sc form, unless other components are added, such as RNA and lipids.^[26] These other components, termed cofactors, may form part of the infectious prion, or they may serve as catalysts for the replication of a protein-only prion.

Viral hypothesis

This hypothesis postulates that an infectious viral agent is the cause of the disease. Evidence for this hypothesis is as follows:

• Incubation time is comparable to a lentivirus
• Strain variation of different isolates of PrP^Sc[27]
• An increasing titre of PrP^Sc as the disease progresses suggests a replicating agent.

Epidemiology

These spontaneous disorders in humans are very rare, affecting only about one person per million worldwide each year. However, transmissible spongiform encephalopathies can reach epidemic proportions, as was seen in the UK BSE outbreak of the 1980s and 1990s. It is very hard to map the spread of the disease due to the difficulty of identifying individual strains of the prions. This means that, if animals at one farm begin to show the disease after an outbreak on a nearby farm, it is very difficult to determine whether it is the same strain affecting both herds—suggesting transmission—or if the second outbreak came from a completely different source.

Possible cure or vaccine and diagnosis

There continues to be a very practical problem with diagnosis of prion diseases, including BSE and CJD. They have an incubation period of months to decades during which there are no symptoms, even though the pathway of converting the normal brain PrP protein into the toxic, disease-related PrP^Sc form has started. At present, there is virtually no way to detect PrP^Sc reliably except by examining the brain using neuropathological and immunohistochemical methods after death. Accumulation of the abnormally folded PrP^Sc form of the PrP protein is a characteristic of the disease, but it is present at very low levels in easily accessible body fluids like blood or urine. Researchers have tried to develop methods to measure PrP^Sc, but there are still no fully accepted methods for use in materials such as blood.

In 2010, a team from New York described detection of PrP^Sc even when initially present at only one part in a hundred billion (10⁻¹¹) in brain tissue. The method combines amplification with a novel technology called Surround Optical Fiber Immunoassay (SOFIA) and some specific antibodies against PrP^Sc. After amplifying and then concentrating any PrP^Sc, the samples are labelled with a fluorescent dye using an antibody for specificity and then finally loaded into a micro-capillary tube. This tube is placed in a specially constructed apparatus so that it is totally surrounded by optical fibres to capture all light emitted once the dye is excited using a laser. The technique allowed detection of PrP^Sc after many fewer cycles of conversion than others have achieved, substantially reducing the possibility of artefacts, as well as speeding up the assay. The researchers also tested their method on blood samples from apparently healthy sheep that went on to develop scrapie. The animals’ brains were analysed once any symptoms became apparent. The researchers could therefore compare results from brain tissue and blood taken once the animals exhibited symptoms of the diseases, with blood obtained earlier in the animals’ lives, and from uninfected animals. The results showed very clearly that PrP^Sc could be detected in the blood of animals long before the symptoms appeared.^[28][29]

Recent research from the University of Toronto and Caprion Pharmaceuticals has discovered one possible avenue that might lead to quicker diagnosis, a vaccine or possibly even treatment for prion diseases. The abnormally folded proteins that cause the disease have been found to expose a side chain of amino acids that the properly folded protein does not expose. Antibodies specifically coded to this side-chain amino acid sequence have been found to stimulate an immune response to the abnormal prions and leave the normal proteins intact.^[30]

Another idea involves using custom peptide sequences. Since some research suggests prions aggregate by forming beta barrel structures, work done in vitro has shown that peptides made up of beta barrel-incompatible amino acids can help break up accumulations of prion.

A third idea concerns genetic therapy, whereby the gene for encoding protease-resistant protein is considered to be an error in several species, and therefore something to be inhibited.

See also

• Proteopathy
• Prion

Further reading

• Deadly Feasts: The "Prion" Controversy and the Public's Health,^[31] by Richard Rhodes
• The Pathological Protein: Mad Cow, Chronic Wasting, and Other Deadly Prion Diseases, Phillip Yam, 2003, Springer, ISBN 0-387-95508-9
• The Family That Couldn't Sleep by D. T. Max provides a history of prion diseases.
• Fatal Flaws: How a Misfolded Protein Baffled Scientists and Changed the Way We Look at the Brain, by Jay Ingram, 2012, HarperCollins Publishers.

References

• This entry incorporates public domain text originally from the National Institute of Neurological Disorders and Stroke, National Institutes of Health and the U.S. National Library of Medicine

External links

• Transmissible spongiform encephalopathy at DMOZ