Transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of rare, progressive, incurable, and invariably fatal conditions that cause degeneration of the nervous system in humans and other animals, such as cattle and sheep. Prion diseases are caused by abnormally shaped proteins called prions, an idea once considered radical, but now well supported by evidence. Prions consist of a protein called the major prion protein (PrP). Misshapen PrP conveys its abnormal structure to native PrP molecules by a crystallization-like seeding process (a process where misfolded proteins convert normal ones into the same abnormal shape). Because PrP is continuously produced by a cell and the abnormal proteins stick to each other, they accumulate in the brain, damaging neurons and eventually causing disease.
Prion diseases cause worsening mental and physical deterioration over time, such as confusion, trouble waking, and loss of coordination. A key pathologic characteristic of prion diseases is the formation of small empty spaces (vacuoles) throughout various parts of the central nervous system, like the brain and spinal cord, giving the tissue a sponge-like appearance under a microscope. Affected regions also show a buildup of misfolded PrP, abnormal growth of support cells (gliosis), and the loss of neurons.
In animals, prion diseases include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle (popularly known as "mad cow disease"), chronic wasting disease (CWD) in deer and elk, and others. In humans, they include Creutzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker syndrome, fatal familial insomnia, kuru, and variably protease-sensitive prionopathy. Creutzfeldt–Jakob disease has been divided into four subtypes: sporadic (idiopathic), hereditary, iatrogenic, and variant. These diseases form a spectrum of related conditions with overlapping signs and symptoms.
Prion diseases are unusual because they can be genetic, infectious, or idiopathic. Genetic (inherited) prion diseases result from rare mutations in PRNP, the gene that codes for PrP. Unlike conventional infectious diseases, which are spread by agents with a DNA or RNA genome (such as viruses or bacteria), prion diseases are transmitted by prions, the active material of which is solely abnormal PrP. Infection can occur when the organism is exposed to prions through consuming contaminated food or via iatrogenic means (such as treatment with biological material that is accidentally contaminated with prions). The variant form of Creutzfeldt–Jakob disease in humans is caused by exposure to BSE prions. While prion diseases spread relatively easily among animals, transmission to humans is very rare. Most people who develop prion disease were never exposed to an infected animal or contaminated material; in the majority of cases, there is no identifiable cause. Sporadic prion diseases occur in the absence of a mutation in the gene for PrP or a source of infection.
Although research has shown that the ability of prions to cause infection depends on the shape of abnormal PrP, auxiliary substances likely contribute to their formation and/or infectivity. In a protein misfolding cyclic amplification (PMCA) assay, purified PrPC cannot convert into the infectious PrP form, unless other components are added, such as a polyanion (usually RNA) and lipids. Other components, known as cofactors, may form part of the infectious prion, or act as catalysts for the replication of a protein-only prion. Considering that 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.
Classification Prion diseases can be classified according to the characteristics of the prions that are involved in each type of disease. PrPC refers to "Cellular" PrP, the normal form of the protein that is not misfolded. PrPSc refers to the scrapie-associated form of PrP, Other generic terms for disease-associated PrP are PrPRes ("Res" stands for "Resistant" to protease), and PrPD ("D" for "Disease"). In the Table below, different prion types are classified based on the disease to which they are linked. Differences in shape among the different prion protein forms are incompletely understood, although new methods such as cryo-electron microscopy are beginning to address this problem.
+ Known spongiform encephalopathies ICTVdb Code Disease name Natural host Prion name PrP isoform Ruminant Non-human mammals 90.001.0.01.001. Scrapie Sheep and goats 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) Cats FSE prion PrPFSE No 90.001.0.01.006. Exotic ungulate encephalopathy (EUE) Nyala and greater kudu EUE prion PrPEUE YesCamel spongiform encephalopathy (CSE)CamelPrPCSE Yes Human diseases 90.001.0.01.007. Kuru Humans 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 insomnia (FFI) FFI prion PrPFFI No Familial spongiform encephalopathy
Pathology
The degenerative tissue damage caused by prion disease in the nervous system is characterized by four features:
Spongiform change (the presence of many small vacuoles) The death of neurons Astrocytosis (abnormal increase in the number of astrocytes) Deposits of abnormal PrP (some of which have the characteristics of amyloid).
These neuropathological features have long been used to diagnose of prion diseases. However, the specific patterns can vary between cases and within different regions of the central nervous system. In humans, prion diseases with different genetic or infectious causes often show distinct pathological features.
For instance, amyloid plaque formation is uncommon in most prion diseases, but is more frequently observed in certain diseases, such as kuru and variant Creutzfeldt–Jakob disease (vCJD). In rare cases, prion diseases may show tauopathy similar to that seen in Alzheimer's disease, highlighting the variability in disease presentations.
Despite this variation, all prion diseases share the common feature of abnormal prion protein accumulation in the nervous system.
Signs and symptoms The clinical signs of prion diseases in humans vary, but the most common signs, especially of sporadic Creutzfeldt–Jakob disease (CJD) include:
Rapidly progressive dementia Behavioral abnormalities and psychiatric symptoms Loss of coordination and/or an unsteady gait (ataxia) Involuntary jerking movements (myoclonus). Unusual sensations, insomnia, and confusion
Prion diseases typically progress rapidly once symptoms appear. For example, the average survival time for people with CJD is about six months, although some individuals may live for a year or longer. All prion diseases are ultimately fatal.
Research on inherited and acquired (infectious) prion disease shows that this short symptomatic period is usually preceded by a long silent phase, during which the abnormal prion proteins gradually accumulate in the brain without causing noticeable symptoms. In some cases this silent phase can last for decades; for instance, the incubation period for kuru can exceed 50 years.
Because the signs and symptoms of prion diseases vary widely and often resemble those of other neurological disorders, diagnosis based on clinical features alone is challenging.
Genetics Only 10–15% of human prion disease cases are heritable; most of them occur sporadically, that is, in the absence of known genetic mutations or infection. However, discovery of the gene involved in heritable prion diseases was a critical event in linking abnormalities of the prion protein to genetic, infectious and idiopathic prion diseases. All familial forms of prion disease are caused by inherited mutations in the PRNP gene, which codes for PrP.
Mutations in the PRNP gene can cause prion diseases. These include:
Point mutations that alter a single amino acid Insertions or repeat expansions that lengthen the protein Mutations that lead to premature stop codons
These mutations increase the likelihood that the prion protein (PrP) will misfold into the wrong shape and accumulate in the nervous system. Different mutations can cause prion diseases with different clinical and pathological characteristics.
The normal function of PrP is not fully understood, but it is believed to play a role in cellular processes and is widely expressed throughout the body, particularly in the nervous system. When the PRNP gene is inactivated in animals such as mice, cattle and goats, the PrP-deficient animals are resistant to prion infection. Other mammals, like canids, also appear to be immune against prion infection. Although the absence of a functional PRNP gene can result in changes in various tissues, the animals are viable and appear to be relatively normal, at least at young ages.
Infectivity Scrapie was suspected to be infectious among sheep in the earliest days from which reliable reports are available. However, it wasn't until the 1930s that the inoculation experiments of Jean Cuillé and Paul-Louis Chelle convincingly demonstrated the infectivity of scrapie (see History, below).
The 1959 exhibition at the Wellcome Medical Museum in London featured the neuropathology of kuru, provided by Igor Klatzko of the NINDS . Whilst attending that exhibit, William Hadlow recognised striking similarities between the neuropathology of scrapie and kuru.
As a consequence Hadlow wrote to D. Carleton Gajdusek enclosing in that correspondence his letter to the Lancet, which recommended injecting primates with infected tissue. The shared features of these human and nonhuman diseases prompted Gajdusek to conduct a series of experiments in which he demonstrated that human spongiform encephalopathies are transmissible to nonhuman primates. His research group reported the transmissibility of kuru in 1966, Creutzfeldt–Jakob disease (CJD) in 1968, and Gerstmann–Sträussler–Scheinker syndrome (GSS) in 1981. These experiments showed that human spongiform encephalopathies, like those in nonhuman species, can be infectious; because the diseases have an unusually long incubation period following exposure to the infectious agent, the agent was sometimes referred to as a 'slow virus'. The infectious agent was not shown with reasonable certainty to be primarily a protein until the work of Stanley Prusiner gave rise to the prion concept in 1982.
Infectious prion diseases in humans are uncommon and decreasing in incidence. Iatrogenic versions have been recognized since the 1980's: Creutzfeldt–Jakob disease has been inadvertently transmitted to patients via injections of growth hormone harvested from human cadaveric pituitary glands, via cadaveric dural allografts, and (more rarely) via corneal transplants, transfusion of blood products, and exposure to contaminated instruments used for brain surgery. Prions can survive heating in the autoclave, a method used for the conventional sterilization of surgical instruments. For this reason, special precautions need to be taken to ensure the complete sterility of neurosurgical instruments.