Transmissible spongiform encephalopathy

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, 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 characterised 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. stain for PrP; Nissl counterstain (blue); scale bar = 100 microns (0.1mm). ==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. 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 (PrPSc) 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. 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 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, For this reason, special precautions need to be taken to ensure the complete sterility of neurosurgical instruments. Dietary consumption of affected animal parts can transmit prion disease, especially in nonhuman species in which infectious prion diseases are relatively common. In these instances, how the agent gains wider access to the body is not entirely clear; besides the apparent transmission of prions via the alimentary tract, transmissible spongiform encephalopathies may be naturally acquired when prion-containing material comes in contact with damaged tissues such as the gums, skin, or conjunctiva. Early studies suggest that plants can be vessels for prion transmission if an infected plant is consumed. It was demonstrated in certain plant species, such as those that animals feed on, like alfalfa and barley, among others. The roots can absorb prions released into the soil from previously deceased, infected animals and transfer them throughout the plant. In turn, this can infect the animal that consumes the prion-containing species. In humans, infection via consumption is very rare, two well-known examples being kuru and variant Creutzfeldt-Jakob disease (vCJD). With the cessation of ritual cannibalism, new cases of Kuru slowly ceased to appear. Prions cannot be transmitted through the air, through touching, or by most other forms of casual contact. However, they may be transmitted through contact with infected tissue, bodily 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. 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. ==Other hypotheses==

The infectious protein hypothesis has become the prevailing explanation for the causation of prion diseases. and another proposed by Frank O. Bastian holds that Spiroplasma infection, specifically Spiroplasma mirum, is a cause of transmissible spongiform encephalopathies. However, no alternative hypothesis has garnered sufficient support to displace the prion paradigm. ==Diagnosis==

The variable presentation of prion diseases and their rapid progression following the appearance of signs and symptoms present a special challenge for diagnosis. Because the early signs of disease can mimic those in other brain disorders, the diagnosis of prion disease is often delayed. Although many of the changes detected by these tests occur in other diseases, combining the test results can establish the presence of prion disease with high Sensitivity and specificity. False positive diagnoses, though rare, are still possible; therefore, definitive diagnosis of prion diseases requires direct examination of brain tissue. ==Treatment==

There are currently no known ways to cure or prevent prion disease. Supportive care is the only option for easing the burden of the disease in affected individuals. Certain medications, such as PSPs, tetracycline, and doxicycline, have been studied experimentally to treat CJD, but their results vary and are generally disappointing. PRN100, a monoclonal antibody, has been overlooked as an emerging treatment that has been shown to lengthen the lifespan of lab mice to a normal lifespan, their effectiveness in humans is still being studied. ==Epidemiology==

Prion diseases are unique in medicine in that they can be sporadic, genetic, or infectious in origin. Of these, approximately 85% are sporadic, 10-15% are genetic, and less than 1% are acquired by infection. Analyses in several countries suggest that the incidence of sCJD has risen in recent years. This increase may be due in part to improved detection of the disease, although the growing elderly population is also a possible factor. Genetic (heritable) human prion diseases are caused by changes in the PRNP gene, which codes for PrP. With the cessation of endocannibalism beginning in the 1950s, the number of cases began to decline, and today the disease is considered to be eradicated. Of the approximately 500 cases of known iatrogenic CJD, most have been recipients of cadaveric pituitary hormones (200 cases, mostly in France) or cadaveric dura mater grafts (over 200 cases, mostly in Japan). In nonhuman species, the epidemiology of prion diseases differs from that in humans in that most cases are infectious in origin. CWD was first identified in captive cervids in Colorado (USA) in 1967, and its distribution has since expanded to include many areas of North America as well as other countries. ==History==

First reports of scrapie in sheep The early history of transmissible spongiform encephalopathies is essentially the history of scrapie. but it is unclear if these were truly transmissible spongiform encephalopathies. The ascertainable history of transmissible spongiform encephalopathies begins with a German language description of scrapie in 1750 Discovery of spongiform change in scrapie Another key event in the history of transmissible spongiform encephalopathies was the discovery of spongiform change (vacuolation) in the nervous system of sheep by Charles Besnoit and colleagues in the late 1890s. Discovery of human spongiform encephalopathy Hans Gerhard Creutzfeldt presented a case report of an unusual neurodegenerative disease in 1920, and this was followed by a description of five cases in 1921 that Alfons Maria Jakob felt were similar to Creutzfeldt's. Walther Spielmeyer in 1922 then christened the disease "Creutzfeldt-Jakob disease". Later, researchers found that Creutzfeldt's original case was likely not a spongiform encephalopathy, but that two of Jakob's first five cases, which were confirmed as what is now called Creutzfeldt-Jakob disease. The transmissibility of spongiform encephalopathies to humans was further substantiated by the BSE crisis and the discovery of iatrogenic forms of prion disease (see Epidemiology, above). Evidence that the infectious agent is unusual In the 1960s, researchers began to confirm longstanding suspicions that the TSEs were caused by an extraordinary infectious agent: Iain Pattison demonstrated the resistance of the scrapie agent to heat and formaldehyde (which destroy most microbes and viruses) and, using ultraviolet and electron irradiation, Tikvah Alper concluded that the agent was extremely small, and that it was unlikely that it replicated via nucleic acids. Griffith's 'second way' proposed that a normally produced cellular protein might adopt an abnormal shape that replicates by converting like proteins into the same shape, a hypothesis that anticipated the formalization of the prion concept in the 1980s. The prion principle is established In 1982, Stanley Prusiner coined the word 'prion' to refer to infectious agents that consisted primarily or exclusively of proteins. Research in the following years demonstrated that PrP is normally produced in the body and that mutations of PRNP are associated with prion diseases. In the 21st century, this research has expanded with the discovery that several (non-infectious) diseases involving the accumulation of abnormal proteins may be caused by a similar molecular mechanism. These include degenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Lewy body dementia, tauopathies, systemic amyloidoses and others. ==See also==