Prion
A prion is a hypothesized 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 by exposure to an already misfolded protein, leading to an abnormal three-dimensional structure that can propagate misfolding in other proteins.
The term prion comes from "proteinaceous infectious particle". Unlike other infectious agents such as viruses, bacteria, and fungi, prions do not contain nucleic acids. Prions are mainly twisted isoforms of the major prion protein, a naturally occurring protein with an uncertain function. They are the hypothesized cause of various diseases, including scrapie in sheep, chronic wasting disease in deer, bovine spongiform encephalopathy in cattle, and Creutzfeldt–Jakob disease 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. Misfolded proteins are also associated with other neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, 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 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 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, 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 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, one disulfide bond, a molecular mass of 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 ions 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, which cleaves the glycophosphatidylinositol 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
The infectious isoform of PrP, known as PrPSc, or simply the prion, is able to convert normal PrPC proteins into the infectious isoform by changing their conformation, or shape; this, in turn, alters the way the proteins interact. PrPSc always causes prion disease. PrPSc has a higher proportion of β-sheet structure in place of the normal α-helix structure. Several highly infectious, brain-derived PrPSc structures have been discovered by cryo-electron microscopy. Another brain-derived fibril structure isolated from humans with Gerstmann-Straussler-Schienker syndrome has also been determined. All of the structures described in high resolution so far are amyloid fibers in which individual PrP molecules are stacked via intermolecular beta sheets. However, 2-D crystalline arrays have also been reported at lower resolution in ex vivo preparations of prions. In the prion amyloids, the glycolipid anchors and asparagine-linked glycans, when present, project outward from the lateral surfaces of the fiber cores. Often PrPSc is bound to cellular membranes, presumably via its array of glycolipid anchors, however, sometimes the fibers are dissociated from membranes and accumulate outside of cells in the form of plaques. The end of each fiber acts as a template onto which free protein molecules may attach, allowing the fiber to grow. This growth process requires complete refolding of PrPC. Different prion strains have distinct templates, or conformations, even when composed of PrP molecules of the same amino acid sequence, as occurs in a particular host genotype. Under most circumstances, only PrP molecules with an identical amino acid sequence to the infectious PrPSc are incorporated into the growing fiber. However, cross-species transmission also happens rarely.PrPres
Protease-resistant PrPSc-like protein is the name given to any isoform of PrPc that is structurally altered and converted into a misfolded proteinase K-resistant form. To model conversion of PrPC to PrPSc in vitro, Kocisko et al. showed that PrPSc could cause PrPC to convert to PrP, res under cell-free conditions. However, the authors state that their results do not rule out the involvement of other non-PrP constituents such as nucleic acids. Soto et al. demonstrated sustained amplification of PrPres and prion infectivity by a procedure involving cyclic amplification of protein misfolding. The term "PrPres" may refer either to protease-resistant forms of PrPSc, which is isolated from infectious tissue and associated with the transmissible spongiform encephalopathy agent, or to other protease-resistant forms of PrP that, for example, might be generated in vitro. Accordingly, unlike PrPSc, PrPres may not necessarily be infectious.Normal function of PrP
The physiological function of the prion protein remains poorly understood. While data from in vitro experiments suggest many dissimilar roles, studies on PrP knockout mice have provided only limited information because these animals exhibit only minor abnormalities. Research in mice has found that the cleavage of PrP in peripheral nerves causes the activation of myelin repair in Schwann cells, and that the lack of PrP proteins causes demyelination in those cells.PrP and regulated cell death
MAVS, RIP1, and RIP3 are prion-like proteins found in other parts of the body. They also polymerise into filamentous amyloid fibers that initiate regulated cell death in the case of a viral infection to prevent the spread of virions to other, surrounding cells. There is evidence that PrP and pathogenic PrPSc contribute to ferroptosis sensitivity, a condition that is enhanced by RAC3 expression.A review of evidence in 2005 suggested that PrP may have a normal function in the maintenance of long-term memory. As well, a 2004 study found that mice lacking genes for normal cellular PrP protein show altered hippocampal long-term potentiation. A recent study that also suggests why this might be the case, found that neuronal protein CPEB has a similar genetic sequence to yeast prion proteins. The prion-like formation of CPEB is essential for maintaining long-term synaptic changes associated with long-term memory formation.PrP and stem cell renewal
A 2006 article from the Whitehead Institute for Biomedical Research indicates that PrP expression on stem cells is necessary for an organism's self-renewal of bone marrow. The study showed that all long-term hematopoietic stem cells express PrP on their cell membrane and that hematopoietic tissues with PrP-null stem cells exhibit increased sensitivity to cell depletion.There is some evidence that PrP may play a role in innate immunity, as the expression of PRNP, the PrP gene, is upregulated in many viral infections and PrP has antiviral properties against many viruses, including HIV.