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Prions - short for proteinaceous infectious particle - are infectious self-reproducing protein structures. Though their exact mechanisms of action and reproduction are still unknown, it is now commonly accepted that they are responsible for a number of previously known but little-understood diseases generally classified under transmissible spongiform encephalopathy (TSEs) diseases, including scrapie (a disease of sheep), kuru (found in members of the cannibalistic Foré tribe in Papua New Guinea), and bovine spongiform encephalopathy (mad cow disease). These diseases affect the structure of brain tissue and are all fatal and untreatable.
Prions were first hypothesized in 1982 by Stanley B. Prusiner of UCSF, who was awarded the Nobel Prize in physiology or medicine in 1997 for the discovery. Prusiner formed the word "prion" from a combination of the words "proteinaceous infectious particle".
Prior to Prusiner's insight, all known pathogens ( bacteria, viruses, etc.) contained nucleic acidA nucleic acid is a complex, high-molecular-weight biochemical macromolecule composed of nucleotide chains that convey genetic information. The most common nucleic acids are deoxyribonucleic acid ( DNA) and ribonucleic acid ( RNA). Nucleic acids are founds, which enable reproduction. The prion hypothesis was developed to explain why the mysterious infectious agent causing Creutzfeldt-Jakob diseaseCreutzfeldt-Jakob Disease (CJD is a lethal brain disorder characterized by memory loss, jerky movements, gait disorder, rigid posture, and seizures due to a rapid loss of cerebral cells caused by transmissible proteins called prions. The disease is correc resisted ultraviolet radiation (which breaks down nucleic acids) but responded to agents that disrupt proteins. This hypothesis was originally highly controversial, because it seemed to contradict the "central dogma of modern biology," which asserts that all living organisms use nucleic acids to reproduce. Prusiner's idea that a protein containing no DNA could reproduce itself was initially met with skepticism, but evidence has steadily accumulated in support of the hypothesis, and it is now widely accepted. Rather than contradicting the central role of DNA, however, the prion hypothesis suggests a special and possibly exceptional case in which merely changing the shape of a protein (without changing its amino acidIn chemistry, an amino acid is any molecule that contains both amino and carboxylic acid functional groups. In biochemistry, this shorter and more general term is frequently used to refer to alpha amino acids: those amino acids in which the amino and carb sequence) can alter its biological properties. The actual reproduction of the protein is still carried out by the ribosomeA ribosome is an organelle composed of rRNA (synthesized in the nucleolus) and ribosomal proteins. It translates mRNA into a polypeptide chain (e. a protein). It can be thought of as a factory that builds a protein from a set of genetic instructions., while the infectious form of the prion protein only transfers the pathological conformationIn chemistry, the conformation of a molecule is its spatial configuration. Examples of cyclohexane conformations: Chemistry. to the prions synthesized by the cell.
A breakthrough occurred when researchers discovered that the infectious agent consisted mainly of a specific protein, which Prusiner called PrP (an abbreviation for "prion protein"). This protein is found in the membranesA component of every biological cell, the cell membrane (or plasma membrane is a thin and structured bilayer of phospholipid and protein molecules that encapsulate the cell. It separates a cell's interior from its surroundings and controls what moves in a of normal cellsstained for keratin The cell is the structural and functional unit of all living organisms. Some organisms, such as bacteria, are unicellular, consisting of a single cell. Other organisms, such as humans, are multicellular, (humans have an estimated 100,0 (its precise function is not known), but an altered shape distinguished the infectious agent. The normal one is called PrPC, while the infectious one is called PrPSC (the 'C' refers to 'cellular' PrP, while the 'SC' refers to ' scrapie', a prion disease occurring in sheep). It is hypothesized that the distorted protein somehow induces normal PrP structure to also become distorted, producing a chain reaction that both propagates the disease and generates new infectious material. Since the original hypothesis was proposed, a gene for the PrP protein has been isolated (the PRNP gene), several mutations that cause the variant shape have been identified and successfully cloned, and studies using genetically altered mice have bolstered the prion hypothesis. The evidence in support of the hypothesis is quite strong now, but not incontrovertible.
In Prusiner's second Scientific American article, he proposed a mechanism for prion propagation that does not require direct action of a prion protein on a normal protein. The suggestion there is that both N, the normal protein, and P, the prion protein, are a product of a post-translational metabolic pathway that forks, leading to either N or P. The presence of P has a negative feedback effect on the fork yielding N, so that P causes less and less N to be made, and more and more P. (For the Creutzfeld-Jakob prion PrP, N corresponds to PrPC, and P corresponds to PrPSC.)
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 pituitary glands, and from instruments used for brain surgery (prions can survive the " autoclave" sterilization process used for most surgical instruments). It is also believed that 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. Laws in developed countries now proscribe the use of rendered ruminant proteins in ruminant feed as a precaution against the spread of prion infection in cattle and other ruminants.
The reason prions are not detected by the immune system is that their "safe" form is already present from birth in the body. The only distinction the "dangerous" prions have is that they are folded slightly differently. Prions infect the nerve lining of neural cells, forming an aggregate which ultimately destroys nerve cells. Depending on the area of the brain which they infect the symptoms can be different. For example, infecting the cerebellum causes impairment of movement. Infecting the cerebral cortex results in a decrease in memory and mental agility.
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