A prion ( ) is a misfolded protein that induces folding problems in normal variants of the same protein, leading to cellular death. Prions are responsible for prion diseases, which are fatal and transmissible neurodegenerative diseases affecting animals, including humans. These proteins can misfold sporadically, due to genetic mutations, or through exposure to an already misfolded protein, leading to an abnormal three-dimensional structure that can propagate misfolding in other proteins. The term prion derives from "proteinaceous infectious particle". Unlike other infectious agents such as viruses, bacteria, and fungi, prions do not contain nucleic acids (DNA or RNA). Prions are primarily twisted isoforms of the major prion protein (PrP), a naturally occurring protein with an uncertain function. They are the hypothesized cause of various diseases, including scrapie in sheep, chronic wasting disease (CWD) in deer, bovine spongiform encephalopathy (BSE) in cattle (mad cow disease), and Creutzfeldt–Jakob disease (CJD) in humans. All known prion diseases in mammals affect the structure of the brain or other neural tissues. These diseases are progressive, have no known effective treatment, and are invariably fatal. Most prion diseases were thought to be caused by PrP until 2015 when a prion form of alpha-synuclein was linked to multiple system atrophy (MSA). Misfolded proteins are also linked to other neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), which have been shown to originate and progress by a prion-like mechanism. Prions are a type of intrinsically disordered protein that continuously changes conformation unless bound to a specific partner, such as another protein. Once a prion binds to another in the same conformation, it stabilizes and can form a fibril, leading to abnormal protein aggregates called amyloids. These amyloids accumulate in infected tissue, causing damage and cell death. The structural stability of prions makes them resistant to denaturation by chemical or physical agents, complicating disposal and containment, and raising concerns about (physician caused) iatrogenic spread through medical instruments.
Etymology and pronunciation The word prion, coined in 1982 by Stanley B. Prusiner, is derived from protein and infection, hence prion. It is short for "proteinaceous infectious particle", in reference to its ability to self-propagate and transmit its conformation to other proteins. Its main pronunciation is , although , as the homographic name of the bird (prions or whalebirds) is pronounced, is also heard. In his 1982 paper introducing the term, Prusiner specified that it is "pronounced pree-on".
Prion protein
Structure
Prions consist of a misfolded form of major prion protein (PrP), a protein that is a natural part of the bodies of humans and other animals. The PrP found in infectious prions has a different structure and is resistant to proteases, the enzymes in the body that can normally break down proteins. The normal form of the protein is called PrPC, while the infectious form is called PrPSc – the C refers to 'cellular' PrP, while the Sc refers to 'scrapie', the prototypic prion disease, occurring in sheep. PrP can also be induced to fold into other more-or-less well-defined isoforms in vitro; although their relationships to the form(s) that are pathogenic in vivo is often unclear, high-resolution structural analyses have begun to reveal structural features that correlate with prion infectivity.
PrPC PrPC is a normal protein found on the membranes of cells, "including several blood components of which platelets constitute the largest reservoir in humans". It has 209 amino acids (in humans), one disulfide bond, a molecular mass of 35–36 kDa and a mainly alpha-helical structure. Several topological forms exist; one cell surface form that is anchored via glycolipid, and two transmembrane forms. The normal protein is not sedimentable; meaning that it cannot be separated by centrifuging techniques. It has a complex function, which continues to be investigated. PrPC binds copper(II) ions (those in a +2 oxidation state) with high affinity. This property is supposed to play a role in PrPC's anti-oxidative properties via reversible oxidation of the N-terminal's methionine residues into sulfoxide. Moreover, studies have suggested that, in vivo, due to PrPC's low selectivity to metallic substrates, the protein's anti oxidative function is impaired when in contact with metals other than copper. PrPC is readily digested by proteinase K and can be liberated from the cell surface by the enzyme phosphoinositide phospholipase C (PI-PLC), which cleaves the glycophosphatidylinositol (GPI) glycolipid anchor. PrP plays an important role in cell-cell adhesion and intracellular signaling in vivo, and may therefore be involved in cell-cell communication in the brain.
PrPSc
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