Because prions are proteins and not viruses or bacteria, they are small enough to penetrate the blood brain barrier, which normally keeps disease out of the brain. As a result, these plaques build up in neurons, causing mental illness and eventually death.
To elaborate on Halcyon&on's good but potentially misleading write-up, it should be pointed out that not all victims of prion diseases are found to have the plaque deposits in their brains. When these amyloid plaques were first discovered, they were thought to be the cause of death, but this theory was quickly discarded when it was established that only about 15% of all CJD victims had them to a severe degree. Subsequently, it became apparent that there was an inverse relation between the extent of the plaques and the infectiousness of the brain tissue found in post-mortem samples. Furthermore, those with the most severe spongiform encephalopathy were the least likely to have plaque deposits.
These plaques consist of PrP27-30, a fragmented form of the abnormal prion mutation (known as PrPsc). The term PrP, which refers to the abormal protein, stands for protease-resistant protein, meaning that the proteolytic enzyme Protease K has no effect on it. However, where these plaques are concerned, this apparently isn't the case. The presence of these plaques indicate that the Protease K enzyme has had some effect on the PrPsc, reducing it to the smaller, less infectious PrP27-30, which has the tendency to accumulate in amyloid plaques. These plaques are found most commonly among victims of genetically inherited prion diseases, and are in many cases believed to be part of a sort of coping mechanism, actually enabling the patient to live longer while suffering from the disease. Post-mortem analysis of these plaques have shown that they often consist of even smaller protein fragments than PrP27-30, such as PrP11, which has a molecular weight of 11 kilodaltons.
CJD variants, such as Gerstmann-Straussler-Scheinker disease, which can take anywhere from 1 to 15 years to kill its victims, is always indicated by the presence of PrP plaques, but not always by spongiform encephalopathy. By the same token, non-variant CJD lasts around 3-12 months, and spongiform encephalopathy is always present, while PrP plaques are less common. In cases such as the former, the cause is usually famillial.
The term "prion", while first used to describe the proteinaceous infectious agent causing scrapie, was later used in association with other mammalian transmissible spongiform encephalopathies (TSEs), such as Mad Cow Disease (bovine spongiform encephalopathy, or BSE), Creutzfeldt-Jakob disease (CJD), and kuru (Prusiner, 1998). Later studies identified and confirmed the presence of several prions of various yeasts, including [PSI+], [URE3], and [PIN+]** of Saccharomyces cerevisiae and [Het-s] of Podospora anserina (Wickner et al., 2002).
Yeast prion modes of action have been well-characterized (Wickner et al., 2002). For example, Ure2p** is a protein involved in the a pathway that signals presence of good nitrogen sources, thereby blocking the uptake of allantoic acid (a poor nitrogen source) and a similar molecule, ureidosuccinic acid (USA), by Dal5p. [URE3] is an altered form of native Ure2p; this altered protein is incapable of blocking the uptake of USA, even in the presence of good nitrogen sources. This phenotype is identical to the mutated form of the ure2 gene, but ure2** strains are incapable of forming the [URE3] prion protein.
By contrast, human and mammalian prion models have been rather poorly characterized, mostly due to lack of data surrounding the phenomenon. They were originally described (in 1954) as "slow viruses", given the lack of evidence for any bacterial transmission factor or genetic predisposition to the diseases. Inability to uncover a viral factor and advances in molecular biology later led to the posing of the prion hypothesis in the early 1980s, which is still in the process of building into a theory (covered later).
Much of the frustration found in exploration of mammalian prions stems from the lack of an effective model for most of the diseases. For obvious reasons, it is implausible to examine the steps involved in inducing prion formation in humans, at least in vivo; ethical considerations often slow progress in large animal research. The obvious answer to this conundrum would be a murine model system; after all, mice share approximately 80% or so homology with humans on a genetic basis, and mouse models are effective in studies of hundreds of other diseases, including cancers and genetic disorders. However, a mouse model strain has not yet been developed that can mimic more than small portions of prion disease progression. So far, those small pieces have presented an interesting puzzle; however, until more can be seen together, it seems there will still be questions.
Incidentally, possibly the most vexing piece of the prion puzzle is the simple fact that scientists have not yet found a function for the mammalian prion protein, or PrP, in its native form (PrPc). In fact, very little is known about the function of the gene encoding the protein, except that it is consitutively expressed in adults and heavily regulated during development. Therefore, exploration the mechanism of attack of PrPSc (the altered form) has been largely the result of guesswork.
Human prions have been shown numerous times to form amyloid fibers (reviewed in Prusiner, 1998). This fiber formation takes on an apparently random shape and size, distinguishing it from viral formation (which always follows a particular pattern); however, this pattern is comparable to such disorders as Alzheimer's disease. Amyloid aggregation is also thought to be the root cause of plaque formation in the brain, which is a major defining symptom of most prion diseases. Along this line, anti-prion drugs and anti-Alzheimer's drugs are being co-examined for cross-effectiveness.
The native form of PrP consists of approximately 40% alpha-helices and very few beta-sheet formations. Alpha helices are smaller, fairly flexible, and usually more susceptible to proteases (enzymes that cut other proteins) because of their relatively loose shape. The infectious form of PrP, however, consists of up to 45% beta-sheets and up to 30% alpha-helices. These beta-sheets are more solid, usually larger, and less susceptible to protease activity because of the inaccessibility of the peptide backbone. The region of amyloid formation, or "prion domain", usually falls in one of the larger regions of beta-sheet formation. (Prusiner (1998) remarks on the seeming impossibility of such a huge variation in proteins of the same sequence, but alpha-helices and beta-sheets are formed in the backbone, somewhat regardless of the sequence of the R-groups.) As reiterated exhaustively already, these conformational changes are the cause of the infectivity of PrP.
Mammalian prion diseases affect the brain and neural tissue; because of their small size, they are easily able to pass the blood-brain barrier (a feat not achieved by most bacteria and viruses). Therefore, prion infections directly result in various forms of neural degeneration. Most, but not all, humans affected with prion disease develop dementia, or impairment of brain function (usually associated with cognitive functions). Some develop ataxia, or the gradual loss of movement and coordination. Most, but not all, show evidence of spongiform degeneration upon autopsy; that is, their brains appear outwardly normal, but show necrotic pockets and a softer, porous, almost squishy texture as a result of loss of brain cells. Plaque formation can also occur as a result of amyloid aggregation; this will often occur along the axons of neurons, which may make them feel more solid than they already are.
Current therapies for prion disease are elusive, and consist largely of easing pain and alleviating minor demential symptoms. Quinacrine (FDA approved for treatment of malaria, a disease caused by a pathogen which also passes the blood-brain barrier), chlorpromazine (Thorazine, FDA approved for treatment of schizophrenia), and some of their derivatives have shown promising effects in vitro against the propagation of PrPSc (Korth et al., 2001). However, further investigation is pending.
For what it's worth, there are no known prions of other animals, plants, fungi, protists, or bacteria. Yet.
A list of known and suspected prions, their hosts, and methods of invasion (adapted partially from Prusiner, 1998):
Sources:
If you never read anything else on prions, read Stanley Prusiner's Nobel Prize speech (Prusiner, 1998). This man did much of the definitive work (such as it is), and is a brilliant scientist and orator. It's really heavy reading in parts, and even I didn't bother reading everything, but if ever you needed an overview, his 20-page abridged lecture, published by PNAS, is all you could possibly want.
printable version chaos
Everything2 Help
cooled by dannye
