Transmissible spongiform encephalopathy
Transmissible spongiform encephalopathies ( TSEs), also known as prion diseases, are a group of progressive, incurable, and fatal conditions that are associated with the prion hypothesis and affect the brain and nervous system of many , including , cattle, and sheep. According to the most widespread hypothesis, they are transmitted by , though some other data suggest an involvement of a Spiroplasma infection. Mental and physical abilities deteriorate and many tiny holes appear in the Cerebral cortex causing it to appear like a sponge when brain tissue obtained at autopsy is examined under a microscope. The disorders cause impairment of brain function which may result in memory loss, personality changes, and Ataxia which worsen over time.
TSEs of humans include Creutzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker syndrome, fatal familial insomnia, kuru, variably protease-sensitive prionopathy and familial spongiform encephalopathy. Creutzfeldt-Jakob disease itself has four main forms: sporadic (sCJD), hereditary/familial (fCJD), iatrogenic (iCJD) and variant (vCJD). These conditions form a spectrum of diseases with overlapping signs and symptoms.
TSEs in non-human mammals include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle – popularly known as "mad cow disease" – and chronic wasting disease (CWD) in deer and elk. The variant form of Creutzfeldt–Jakob disease in humans is caused by exposure to bovine spongiform encephalopathy prions.
Unlike other kinds of infectious disease, which are spread by agents with a DNA or RNA genome (such as virus or bacteria), the infectious agent in TSEs is believed to be a prion, composed solely of protein material. Misfolded 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 Iatrogenesis means (e.g., blood transfusion). Most TSEs are sporadic and occur in an animal with no prion protein mutation. Inherited TSE occurs in animals carrying a rare mutation 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 the 1980s and 1990s, bovine spongiform encephalopathy 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. In turn, consumption (by humans) of bovine-derived foodstuff which contained prion-contaminated tissues resulted in an outbreak of variant form of Creutzfeldt–Jakob disease in the 1990s and 2000s.
Prions cannot be transmitted through the air, 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. However, treatment with strong, almost undiluted bleach and/or sodium hydroxide, or heating to a minimum of 134 °C, does destroy prions.
Classification
| + Known spongiform encephalopathies | |||||
| 90.001.0.01.001. | Scrapie | Sheep and | Scrapie prion | PrPSc | Yes |
| 90.001.0.01.002. | Transmissible mink encephalopathy (TME) | Mink | TME prion | PrPTME | No |
| 90.001.0.01.003. | Chronic wasting disease (CWD) | Elk, white-tailed deer, mule deer and red deer | CWD prion | PrPCWD | Yes |
| 90.001.0.01.004. | Bovine spongiform encephalopathy (BSE) commonly known as "mad cow disease" | Cattle | BSE prion | PrPBSE | Yes |
| 90.001.0.01.005. | Feline spongiform encephalopathy (FSE) | FSE prion | PrPFSE | No | |
| 90.001.0.01.006. | Exotic ungulate encephalopathy (EUE) | Nyala and Greater Kudu | EUE prion | PrPEUE | Yes |
| Camel spongiform encephalopathy (CSE) | Camel | PrPCSE | Yes | ||
| 90.001.0.01.007. | Kuru | Kuru prion | PrPKuru | No | |
| 90.001.0.01.008. | Creutzfeldt–Jakob disease (CJD) | CJD prion | PrPsCJD | No | |
| Variant Creutzfeldt–Jakob disease (vCJD, nvCJD) | vCJD prionBelieved to be identical to the BSE prion. | PrPvCJD | |||
| 90.001.0.01.009. | Gerstmann-Sträussler-Scheinker syndrome (GSS) | GSS prion | PrPGSS | No | |
| 90.001.0.01.010. | Fatal familial insomnia (FFI) | FFI prion | PrPFFI | No | |
| Familial spongiform encephalopathy |
Signs and symptoms
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.
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 , from cadaver dura mater allografts and from instruments used for brain surgery (Brown, 2000) (prions can survive the "autoclave" sterilization process used for most surgical instruments). 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. 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 encephalopathy 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. 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.
Cause
Genetics
The PRNP gene encodes the prion protein (PrP), which under normal conditions may play a role in transporting copper into cells and protecting neurons. Misfolding of the prion protein leads to the accumulation of pathogenic PrP^Sc, the hallmark of prion diseases, causing progressive neurodegeneration.
Epidemiological surveillance has identified cases of atypical bovine spongiform encephalopathy (BSE) and scrapie in livestock, as well as chronic wasting disease (CWD) in cervids, highlighting the zoonotic potential of prion diseases and their impact on animal and human health.
Protein-only hypothesis
- Infectivity titre correlates with PrPSc levels. However, this is disputed.
- PrPSc is an isomer of PrPC
- Denaturing PrP removes infectivity
- PrP-null mice cannot be infected
- PrPC depletion in the neural system of mice with established neuroinvasive prion infection reverses early spongeosis and behavioural deficits, halts further disease progression and increases life-span.
- Recombinant PrPC expressed in E. coli have been converted into infectious PrPSc without the use of any material of mammalian origin. This was first achieved in 2004 using refolding in concentrated urea, then in 2010 in a PMCA setup.
Multi-component hypothesis
The choice of polyanion can be either sulfated glycans or RNA. The sequence of the RNA matters little (a synthetic poly(A) tract suffices), but it needs to be single-stranded. Artificial prions produced using this poly(A) RNA requires a longer incubation period for the disease to show, suggesting that it is possibly not the best RNA catalyst for prion conversion.
The choice of the lipid is also not very restrictive. Synthetic phospholipid 1-palmitoyl-2-oleoylphosphatidylglycerol (POPG) with normal mouse liver RNA (chosen because it has a more varied sequence than poly(A) but is not from an organ where prions accumulate) is able to catalyze the conversion from recombinant E. coli PrPC to PrPSc without a starting mass of PrPSc: a phenomenon analogous to sporadic TSE. The resulting PrPSc could be propogated using poly(A) RNA and POPG.
Considering the cofactors can be produced by chemical synthesis instead of being sourced solely from infected cases (or any animal at all), it is fair to say that they do not form the infectious part of the prion. However, these catalysts (especially the polyanion) do have a tendency to be included in the prion aggregate, which makes seeding new aggregates easier in vitro. There are also reports of successful PMCA without the need of any polyanion or lipid, mentioned above.
Viral hypothesis
- Brain and cultured neuron cell particles were sorted by infectivity titers using a cellular assay. The most infective parts (p18 and its ASB supernatant) contain very little protein including PrP, though they also contains little of the starting amount of nucleic acids.
- Brain titers exposed to reduced infectivity by >=99%. (This could alternatively be viewed as supportive as the multi-component hypothesis.)
- Existence of immune responses, according to proponents.
- Incubation time is comparable to a lentivirus.
- Strain variation of different isolates of PrPsc. Most importantly, they have different resistances to nuclease, which is not explained by the multi-component hypothesis.
Other hypotheses
There is a theory by Frank O. Bastian that Spiroplasma infection, specifically Spiroplasma mirum, causes TSE. Bastian has repeatedly reported that the ribosomal RNA of this bacterium is found in TSE brain tissue and that experimental infections cause TSE in rodents and deer. Others have consistently failed to replicate his results. Bastian last updated his argument in 2014. No specific rebuttal has been written since.
Diagnosis
In 2010, a team from New York described detection of PrPSc 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 PrPSc. After amplifying and then concentrating any PrPSc, 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 PrPSc 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 PrPSc could be detected in the blood of animals long before the symptoms appeared.
Treatment
Epidemiology
Classic Creutzfeldt-Jakob disease (CJD) was discovered in 1920. It occurs sporadically over the world but is very rare. It affects about one person per million each year. Typically, the cause is unknown for these cases. It has been found to be passed on genetically in some cases. 250 patients contracted the disease through iatrogenic transmission (from use of contaminated surgical equipment). This was before equipment sterilization was required in 1976, and there have been no other iatrogenic cases since then. In order to prevent the spread of infection, the World Health Organization created a guide to tell health care workers what to do when CJD appears and how to dispose of contaminated equipment. The Centers for Disease Control and Prevention (CDC) have been keeping surveillance on CJD cases, particularly by looking at death certificate information.
Chronic wasting disease (CWD) is a prion disease found in North America in deer and elk. The first case was identified as a fatal wasting syndrome in the 1960s. It was then recognized as a transmissible spongiform encephalopathy in 1978. Surveillance studies showed that CWD was endemic among free-ranging deer and elk in northeastern Colorado, southeastern Wyoming and western Nebraska. It was also discovered that CWD may have been present in a proportion of free-ranging animals decades before the initial recognition. In the United States, the discovery of CWD raised concerns about the transmission of this prion disease to humans. It was suspected that many cases of CJD were transmitted by CWD, however the evidence was minimal.
In the 1980s and 1990s, bovine spongiform encephalopathy (BSE or "mad cow disease") spread in cattle at an epidemic rate. The total estimated number of cattle infected was approximately 750,000 between 1980 and 1996 as a result of being fed the processed remains of other cattle. Subsequent human consumption of these infected cattle caused an outbreak of the human form CJD. There was a dramatic decline in BSE when feeding bans were put in place. On May 20, 2003, the first case of BSE was confirmed in North America, suspected to originate from imported BSE-infected cow meat. In the United States, the USDA created safeguards to minimize the risk of BSE exposure to humans.
Variant Creutzfeldt-Jakob disease (vCJD) was discovered in 1996 in England. There is strong evidence to suggest that vCJD was caused by the same prion as bovine spongiform encephalopathy. "Since 1996 and as of August 2013, a total of 229 cases of variant CJD cases have been identified from 11 countries: 177 from the United Kingdom, 27 from France, 4 from Ireland, 4 from the United States, 5 from Spain, 3 in the Netherlands, 2 each from Portugal, Italy and Canada, and 1 each from Japan, Taiwan and Saudi Arabia."
History
See also
- Proteinopathy
- Variably protease-sensitive prionopathy
- This entry incorporates public domain text originally from the National Institute of Neurological Disorders and Stroke, National Institutes of Health [1] and the U.S. National Library of Medicine [2]
External links
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