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.
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 diseases presentation. 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:
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