Prions are
misfolded protein
Protein folding is the physical process by which a protein chain is translated to its native three-dimensional structure, typically a "folded" conformation by which the protein becomes biologically functional. Via an expeditious and reproduci ...
s that have the ability to transmit their misfolded shape onto normal variants of the same protein. They characterize several fatal and transmissible
neurodegenerative diseases
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
in humans and many other animals. It is not known what causes a normal protein to misfold, but the resulting abnormal
three-dimensional structure confers infectious properties by collapsing nearby protein molecules into the same shape.
The word ''prion'' is derived from the term, "proteinaceous infectious particle".
In comparison to all other known infectious agents such as
viroid
Viroids are small single-stranded, circular RNAs that are infectious pathogens. Unlike viruses, they have no protein coating. All known viroids are inhabitants of angiosperms (flowering plants), and most cause diseases, whose respective economi ...
s,
virus
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea.
Since Dmitri Ivanovsky's 1 ...
es,
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
,
fungi
A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...
, and
parasite
Parasitism is a close relationship between species, where one organism, the parasite, lives on or inside another organism, the host, causing it some harm, and is adapted structurally to this way of life. The entomologist E. O. Wilson has ...
s, all of which contain
nucleic acid
Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...
s (
DNA,
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
, or both), the hypothesized role of a protein as an infectious agent stands in contrast.
Prion isoforms of the
prion protein
Major prion protein (PrP), is encoded in the human by the ''PRNP'' gene also known as CD230 (cluster of differentiation 230). Expression of the protein is most predominant in the nervous system but occurs in many other tissues throughout the bod ...
(PrP), whose specific function is uncertain, are hypothesized as the cause of
transmissible spongiform encephalopathies
Transmissible spongiform encephalopathies (TSEs) are a group of progressive and fatal conditions that are associated with prions and affect the brain and nervous system of many animals, including humans, cattle, and sheep. According to the most ...
(TSEs), including
scrapie
Scrapie () is a fatal, degenerative disease affecting the nervous systems of sheep and goats. It is one of several transmissible spongiform encephalopathies (TSEs), and as such it is thought to be caused by a prion. Scrapie has been known since ...
in sheep,
chronic wasting disease
Chronic wasting disease (CWD), sometimes called zombie deer disease, is a transmissible spongiform encephalopathy (TSE) affecting deer. TSEs are a family of diseases thought to be caused by misfolded proteins called prions and include similar dis ...
(CWD) in deer,
bovine spongiform encephalopathy
Bovine spongiform encephalopathy (BSE), commonly known as mad cow disease, is an incurable and invariably fatal neurodegenerative disease of cattle. Symptoms include abnormal behavior, trouble walking, and weight loss. Later in the course of t ...
(BSE) in cattle (commonly known as "mad cow disease") and
Creutzfeldt–Jakob disease
Creutzfeldt–Jakob disease (CJD), also known as subacute spongiform encephalopathy or neurocognitive disorder due to prion disease, is an invariably fatal degenerative brain disorder. Early symptoms include memory problems, behavioral changes, ...
(CJD) in humans.
All known prion diseases in
mammals
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
affect the structure of the
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
or other
neural
In Biology, biology, the nervous system is the Complex system, highly complex part of an animal that coordinates its Behavior, actions and Sense, sensory information by transmitting action potential, signals to and from different parts of its ...
tissue; all are progressive, have no known effective treatment, and are always fatal. Until 2015, all known mammalian prion diseases were caused by the prion protein (PrP); however, in 2015 it was hypothesized that
multiple system atrophy
Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by autonomic dysfunction, tremors, slow movement, muscle rigidity, and postural instability (collectively known as parkinsonism) and ataxia. This is caused by progr ...
(MSA) was caused by a prion form of
alpha-synuclein
Alpha-synuclein is a protein that, in humans, is encoded by the ''SNCA'' gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release.
It is abundant in the brain, while smaller a ...
.
Prions are a type of
intrinsically disordered protein
In molecular biology, an intrinsically disordered protein (IDP) is a protein that lacks a fixed or ordered three-dimensional structure, typically in the absence of its macromolecular interaction partners, such as other proteins or RNA. IDPs rang ...
, which change their conformation unless they are bound to a specific partner such as another protein. With a prion, two protein chains are stabilized if one binds to another in the same conformation. The probability of this happening is low, but once it does the combination of the two is very stable. Then more units can get added, making a sort of "
fibril
Fibrils (from the Latin ''fibra'') are structural biological materials found in nearly all living organisms. Not to be confused with fibers or filaments, fibrils tend to have diameters ranging from 10-100 nanometers (whereas fibers are micro ...
".
Prions form abnormal aggregates of proteins called
amyloids
Amyloids are aggregates of proteins characterised by a fibrillar morphology of 7–13 nm in diameter, a beta sheet (β-sheet) secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the human ...
, which accumulate in infected tissue and are associated with tissue damage and cell death. Amyloids are also responsible for several other neurodegenerative diseases such as
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
and
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
.
A prion disease is a type of
proteopathy
In medicine, proteinopathy (; 'pref''. protein -pathy 'suff''. disease proteinopathies ''pl''.; proteinopathic ''adj''), or proteopathy, protein conformational disorder, or protein misfolding disease refers to a class of diseases in which certa ...
, or disease of structurally abnormal proteins. In humans, prions are believed to be the cause of Creutzfeldt–Jakob disease (CJD),
its variant (vCJD),
Gerstmann–Sträussler–Scheinker syndrome
Gerstmann–Sträussler–Scheinker syndrome (GSS) is an extremely rare, usually familial, fatal neurodegenerative disease that affects patients from 20 to 60 years in age. It is exclusively heritable, and is found in only a few families all over ...
(GSS),
fatal familial insomnia
Fatal insomnia is an extremely rare genetic (and even more rarely, sporadic) disorder that results in trouble sleeping as its hallmark symptom. The problems with sleeping typically start out gradually and worsen over time. Eventually, the patien ...
(FFI), and
kuru
Kuru may refer to:
Anthropology and history
* Kuru (disease), a type of transmissible spongiform encephalopathy associated with the cannibalistic funeral practices of the Fore people
* Kuru (mythology), part of Meithei mythology
* Kuru Kingdom, ...
.
There is also evidence suggesting prions may play a part in the process of Alzheimer's disease, Parkinson's disease, and
amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
(ALS); these have been termed ''prion-like diseases''.
Several
yeast
Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constitut ...
proteins have also been identified as having prionogenic properties,
as well as a protein involved in modification of
synapse
In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell.
Synapses are essential to the transmission of nervous impulses from ...
s during the formation of memories
(see ). Prion replication is subject to
epimutation
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are " ...
and
natural selection
Natural selection is the differential survival and reproduction of individuals due to differences in phenotype. It is a key mechanism of evolution, the change in the heritable traits characteristic of a population over generations. Charle ...
just as for other forms of replication, and their structure varies slightly between species.
Prion aggregates are stable, and this structural stability means that prions are resistant to
denaturation by chemical and physical agents: they cannot be destroyed by ordinary disinfection or cooking. This makes disposal and containment of these particles difficult.
Etymology and pronunciation
The word ''prion'', coined in 1982 by
Stanley B. Prusiner, is derived from protein and infection, hence prion, and is short for "proteinaceous infectious particle",
Lay summary: in reference to its ability to self-propagate and transmit its conformation to other proteins.
Its main pronunciation is ,
although , as the
homograph
A homograph (from the el, ὁμός, ''homós'', "same" and γράφω, ''gráphō'', "write") is a word that shares the same written form as another word but has a different meaning. However, some dictionaries insist that the words must also ...
ic 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
The protein that prions are made of (PrP) is found throughout the body, even in healthy people and animals. However, PrP found in infectious material has a different structure
A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...
and is resistant to protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
s, 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
Scrapie () is a fatal, degenerative disease affecting the nervous systems of sheep and goats. It is one of several transmissible spongiform encephalopathies (TSEs), and as such it is thought to be caused by a prion. Scrapie has been known since ...
', the prototypic prion disease, occurring in sheep. While PrPC is structurally well-defined, PrPSc is certainly polydisperse and defined at a relatively poor level. PrP can be induced to fold into other more-or-less well-defined isoforms in vitro, and their relationship to the form(s) that are pathogenic in vivo is not yet clear.
PrPC
PrPC is a normal protein found on the membranes
A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. Bi ...
of cells, "including several blood components of which platelets
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
constitute the largest reservoir in humans." It has 209 amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s (in humans), one disulfide bond
In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
, a molecular mass of 35–36 kDa
The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...
and a mainly alpha-helical
The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues e ...
structure. Several topological
In mathematics, topology (from the Greek words , and ) is concerned with the properties of a geometric object that are preserved under continuous deformations, such as stretching, twisting, crumpling, and bending; that is, without closing h ...
forms exist; one cell surface form anchored via glycolipid
Glycolipids are lipids with a carbohydrate attached by a glycosidic (covalent) bond. Their role is to maintain the stability of the cell membrane and to facilitate cellular recognition, which is crucial to the immune response and in the connec ...
and two transmembrane
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
forms. The normal protein is not sedimentable; meaning that it cannot be separated by centrifuging techniques. Its function is a complex issue that continues to be investigated. PrPC binds copper
Copper is a chemical element with the symbol Cu (from la, cuprum) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pinkis ...
(II) ion
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
s with high affinity. The significance of this finding is not clear, but it is presumed to relate to PrP structure or function. PrPC is readily digested by proteinase K
In molecular biology Proteinase K (, ''protease K'', ''endopeptidase K'', ''Tritirachium alkaline proteinase'', ''Tritirachium album serine proteinase'', ''Tritirachium album proteinase K'') is a broad-spectrum serine protease. The enzyme was dis ...
and can be liberated from the cell surface in vitro by the enzyme phosphoinositide phospholipase C
Phosphoinositide phospholipase C (PLC, EC 3.1.4.11, triphosphoinositide phosphodiesterase, phosphoinositidase C, 1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase, monophosphatidylinositol phosphodiesterase, phosphatidylinositol phosph ...
(PI-PLC), which cleaves the glycophosphatidylinositol
Glycosylphosphatidylinositol (), or glycophosphatidylinositol, or GPI in short, is a phosphoglyceride that can be attached to the C-terminus of a protein during posttranslational modification. The resulting GPI-anchored proteins play key roles i ...
(GPI) glycolipid anchor. PrP has been reported to play important roles in cell-cell adhesion and intracellular signaling ''in vivo'', and may therefore be involved in cell-cell communication in the brain.
PrPres
Protease-resistant PrPSc-like protein (PrPres) is the name given to any isoform of PrPc which is structurally altered and converted into a misfolded proteinase K
In molecular biology Proteinase K (, ''protease K'', ''endopeptidase K'', ''Tritirachium alkaline proteinase'', ''Tritirachium album serine proteinase'', ''Tritirachium album proteinase K'') is a broad-spectrum serine protease. The enzyme was dis ...
-resistant form ''in vitro''. To model conversion of PrPC to PrPSc in vitro, Saborio ''et al''. rapidly converted PrPC into a PrPres by a procedure involving cyclic amplification of protein misfolding. The term "PrPres" has been used to distinguish between PrPSc, which is isolated from infectious tissue and associated with the transmissible spongiform encephalopathy agent. For example, unlike PrPSc, PrPres may not necessarily be infectious.
PrPSc
The infectious isoform
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
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 interconnect. PrPSc always causes prion disease. Although the exact 3D structure of PrPSc is not known, it has a higher proportion of β-sheet
The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gen ...
structure in place of the normal α-helix
The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues e ...
structure. Aggregations of these abnormal isoforms form highly structured amyloid
Amyloids are aggregates of proteins characterised by a Fibril, fibrillar morphology of 7–13 Nanometer, nm in diameter, a beta sheet (β-sheet) Secondary structure of proteins, secondary structure (known as cross-β) and ability to be Staining, ...
fibers, which accumulate to form plaques. The end of each fiber acts as a template onto which free protein molecules may attach, allowing the fiber to grow. Under most circumstances, only PrP molecules with an identical amino acid sequence to the infectious PrPSc are incorporated into the growing fiber. However, rare cross-species transmission is also possible.
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
A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
have provided only limited information because these animals exhibit only minor abnormalities. In research done in mice, it was found that the cleavage of PrP in peripheral nerves causes the activation of myelin
Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...
repair in Schwann cells
Schwann cells or neurolemmocytes (named after German physiologist Theodor Schwann) are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensh ...
and that the lack of PrP proteins caused 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 which initiate regulated cell death in the case of a viral infection to prevent the spread of virions
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea.
Since Dmitri Ivanovsky's 1 ...
to other, surrounding cells.
PrP and long-term memory
A review of evidence in 2005 suggested that PrP may have a normal function in maintenance of long-term memory
Long-term memory (LTM) is the stage of the Atkinson–Shiffrin memory model in which informative knowledge is held indefinitely. It is defined in contrast to short-term and working memory, which persist for only about 18 to 30 seconds. Long-t ...
. As well, a 2004 study found that mice lacking genes for normal cellular PrP protein show altered hippocampal
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, an ...
long-term potentiation
In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons ...
. A recent study that might explain why this is found that neuronal protein CPEB
CPEB, or cytoplasmic polyadenylation element binding protein, is a highly conserved RNA-binding protein that promotes the elongation of the polyadenine tail of messenger RNA. CPEB most commonly activates the target RNA for translation, but ca ...
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
Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...
. The study showed that all long-term hematopoietic stem cell
Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within t ...
s express PrP on their cell membrane and that hematopoietic tissues with PrP-null stem cells exhibit increased sensitivity to cell depletion.
PrP and innate immunity
There is some evidence that PrP may play a role in innate immunity
The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...
, as the expression of PRNP
Major prion protein (PrP), is encoded in the human by the ''PRNP'' gene also known as CD230 (cluster of differentiation 230). Expression of the protein is most predominant in the nervous system but occurs in many other tissues throughout the bod ...
, the PrP gene, is upregulated in many viral infections and PrP has antiviral properties against many viruses, including HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
.
Replication
The first hypothesis that tried to explain how prions replicate in a protein-only manner was the heterodimer
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
model. This model assumed that a single PrPSc molecule binds to a single PrPC molecule and catalyzes its conversion into PrPSc. The two PrPSc molecules then come apart and can go on to convert more PrPC. However, a model of prion replication must explain both how prions propagate, and why their spontaneous appearance is so rare. Manfred Eigen
Manfred Eigen (; 9 May 1927 – 6 February 2019) was a German Biophysical chemistry, biophysical chemist who won the 1967 Nobel Prize in Chemistry for work on measuring fast chemical reactions.
Eigen's research helped solve major problems in ...
showed that the heterodimer model requires PrPSc to be an extraordinarily effective catalyst, increasing the rate of the conversion reaction by a factor of around 1015. This problem does not arise if PrPSc exists only in aggregated forms such as amyloid
Amyloids are aggregates of proteins characterised by a Fibril, fibrillar morphology of 7–13 Nanometer, nm in diameter, a beta sheet (β-sheet) Secondary structure of proteins, secondary structure (known as cross-β) and ability to be Staining, ...
, where cooperativity
Cooperativity is a phenomenon displayed by systems involving identical or near-identical elements, which act dependently of each other, relative to a hypothetical standard non-interacting system in which the individual elements are acting indepen ...
may act as a barrier to spontaneous conversion. What is more, despite considerable effort, infectious monomeric PrPSc has never been isolated.
An alternative model assumes that PrPSc exists only as fibril
Fibrils (from the Latin ''fibra'') are structural biological materials found in nearly all living organisms. Not to be confused with fibers or filaments, fibrils tend to have diameters ranging from 10-100 nanometers (whereas fibers are micro ...
s, and that fibril ends bind PrPC and convert it into PrPSc. If this were all, then the quantity of prions would increase linearly
Linearity is the property of a mathematical relationship (''function'') that can be graphically represented as a straight line. Linearity is closely related to '' proportionality''. Examples in physics include rectilinear motion, the linear r ...
, forming ever longer fibrils. But exponential growth
Exponential growth is a process that increases quantity over time. It occurs when the instantaneous rate of change (that is, the derivative) of a quantity with respect to time is proportional to the quantity itself. Described as a function, a q ...
of both PrPSc and of the quantity of infectious particles is observed during prion disease. This can be explained by taking into account fibril breakage. A mathematical solution for the exponential growth rate resulting from the combination of fibril growth and fibril breakage has been found. The exponential growth rate depends largely on the square root
In mathematics, a square root of a number is a number such that ; in other words, a number whose ''square'' (the result of multiplying the number by itself, or ⋅ ) is . For example, 4 and −4 are square roots of 16, because .
E ...
of the PrPC concentration. The incubation period
Incubation period (also known as the latent period or latency period) is the time elapsed between exposure to a pathogenic organism, a chemical, or radiation, and when symptoms and signs are first apparent. In a typical infectious disease, the i ...
is determined by the exponential growth rate, and in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
data on prion diseases in transgenic mice
A genetically modified mouse or genetically engineered mouse model (GEMM) is a mouse (''Mus musculus'') that has had its genome altered through the use of genetic engineering techniques. Genetically modified mice are commonly used for research or ...
match this prediction. The same square root dependence is also seen in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
in experiments with a variety of different amyloid proteins.
The mechanism of prion replication has implications for designing drugs. Since the incubation period of prion diseases is so long, an effective drug does not need to eliminate all prions, but simply needs to slow down the rate of exponential growth. Models predict that the most effective way to achieve this, using a drug with the lowest possible dose, is to find a drug that binds to fibril ends and blocks them from growing any further.
Researchers at Dartmouth College discovered that endogenous host cofactor molecules such as the phospholipid molecule (e.g. phosphatidylethanolamine) and polyanions
Polyelectrolytes are polymers whose repeating units bear an electrolyte group. Polycations and polyanions are polyelectrolytes. These groups dissociate in aqueous solutions (water), making the polymers charged. Polyelectrolyte properties are th ...
(e.g. single stranded RNA molecules) are necessary to form PrPSc molecules with high levels of specific infectivity ''in vitro'', whereas protein-only PrPSc molecules appear to lack significant levels of biological infectivity.
Transmissible spongiform encephalopathies
Prions cause neurodegenerative disease by aggregating extracellularly within the central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
to form plaques known as amyloids
Amyloids are aggregates of proteins characterised by a fibrillar morphology of 7–13 nm in diameter, a beta sheet (β-sheet) secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the human ...
, which disrupt the normal tissue structure. This disruption is characterized by "holes" in the tissue with resultant spongy architecture due to the vacuole
A vacuole () is a membrane-bound organelle which is present in plant and fungal cells and some protist, animal, and bacterial cells. Vacuoles are essentially enclosed compartments which are filled with water containing inorganic and organic mo ...
formation in the neurons. Other histological changes include astrogliosis
Astrogliosis (also known as astrocytosis or referred to as reactive astrogliosis) is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons from central nervous system (CNS) trauma, infection, ischemia, stroke, a ...
and the absence of an inflammatory reaction. While the incubation period
Incubation period (also known as the latent period or latency period) is the time elapsed between exposure to a pathogenic organism, a chemical, or radiation, and when symptoms and signs are first apparent. In a typical infectious disease, the i ...
for prion diseases is relatively long (5 to 20 years), once symptoms appear the disease progresses rapidly, leading to brain damage and death. Neurodegenerative symptoms can include convulsion
A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a s ...
s, dementia
Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
, ataxia
Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...
(balance and coordination dysfunction), and behavioural or personality changes.
Many different mammalian species can be affected by prion diseases, as the prion protein (PrP) is very similar in all mammals. Due to small differences in PrP between different species it is unusual for a prion disease to transmit from one species to another. The human prion disease variant Creutzfeldt–Jakob disease, however, is thought to be caused by a prion that typically infects cattle, causing bovine spongiform encephalopathy
Bovine spongiform encephalopathy (BSE), commonly known as mad cow disease, is an incurable and invariably fatal neurodegenerative disease of cattle. Symptoms include abnormal behavior, trouble walking, and weight loss. Later in the course of t ...
and is transmitted through infected meat.
All known prion diseases are untreatable and fatal. However, a vaccine developed in mice may provide insight into providing a vaccine to resist prion infections in humans. Additionally, in 2006 scientists announced that they had genetically engineered cattle lacking a necessary gene for prion production – thus theoretically making them immune to BSE, building on research indicating that mice lacking normally occurring prion protein are resistant to infection by scrapie prion protein. In 2013, a study revealed that 1 in 2,000 people in the United Kingdom might harbour the infectious prion protein that causes vCJD.
Until 2015 all known mammalian prion diseases were considered to be caused by the prion protein, PrP; in 2015 multiple system atrophy
Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by autonomic dysfunction, tremors, slow movement, muscle rigidity, and postural instability (collectively known as parkinsonism) and ataxia. This is caused by progr ...
was found to be transmissible and was hypothesized to be caused by a new prion, the misfolded form of a protein called alpha-synuclein
Alpha-synuclein is a protein that, in humans, is encoded by the ''SNCA'' gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release.
It is abundant in the brain, while smaller a ...
.[ The endogenous, properly folded form of the prion protein is denoted PrPC (for ''Common'' or ''Cellular''), whereas the disease-linked, misfolded form is denoted PrPSc (for ''Scrapie''), after one of the diseases first linked to prions and neurodegeneration.] The precise structure of the prion is not known, though they can be formed spontaneously by combining PrPC, homopolymeric polyadenylic acid, and lipids in a protein misfolding cyclic amplification Protein misfolding cyclic amplification (PMCA) is an amplification technique (conceptually like PCR but not involving nucleotides) to multiply misfolded prions originally developed by Soto and colleagues.Saborio, G.P., Permanne, B. and Soto, C. (20 ...
(PMCA) reaction even in the absence of pre-existing infectious prions. This result is further evidence that prion replication does not require genetic information.
Transmission
It has been recognized that prion diseases can arise in three different ways: acquired, familial, or sporadic. It is often assumed that the diseased form directly interacts with the normal form to make it rearrange its structure. One idea, the "Protein X" hypothesis, is that an as-yet unidentified cellular protein (Protein X) enables the conversion of PrPC to PrPSc by bringing a molecule of each of the two together into a complex.
The primary method of infection in animals is through ingestion. It is thought that prions may be deposited in the environment through the remains of dead animals and via urine, saliva, and other body fluids. They may then linger in the soil by binding to clay and other minerals.
A University of California research team has provided evidence for the theory that infection can occur from prions in manure. And, since manure is present in many areas surrounding water reservoirs, as well as used on many crop fields, it raises the possibility of widespread transmission. It was reported in January 2011 that researchers had discovered prions spreading through airborne transmission on aerosol
An aerosol is a suspension (chemistry), suspension of fine solid particles or liquid Drop (liquid), droplets in air or another gas. Aerosols can be natural or Human impact on the environment, anthropogenic. Examples of natural aerosols are fog o ...
particles, in an animal testing
Animal testing, also known as animal experimentation, animal research, and ''in vivo'' testing, is the use of non-human animals in experiments that seek to control the variables that affect the behavior or biological system under study. This ...
experiment focusing on scrapie
Scrapie () is a fatal, degenerative disease affecting the nervous systems of sheep and goats. It is one of several transmissible spongiform encephalopathies (TSEs), and as such it is thought to be caused by a prion. Scrapie has been known since ...
infection in laboratory mice
The laboratory mouse or lab mouse is a small mammal of the order Rodentia which is bred and used for scientific research or feeders for certain pets. Laboratory mice are usually of the species ''Mus musculus''. They are the most commonly used ...
. Preliminary evidence supporting the notion that prions can be transmitted through use of urine-derived human menopausal gonadotropin
Menotropin (also called human menopausal gonadotropin or hMG) is a hormonally active medication for the treatment of fertility disturbances. Frequently the plural is used as the medication is a mixture of gonadotropins. Menotropins are extracted ...
, administered for the treatment of infertility
Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal state ...
, was published in 2011.
Prions in plants
In 2015, researchers at The University of Texas Health Science Center at Houston
The University of Texas Health Science Center at Houston (UTHealth) is a public academic health science center in Houston, Texas, United States. It was created in 1972 by The University of Texas System Board of Regents. It is located in the T ...
found that plants can be a vector for prions. When researchers fed hamsters grass that grew on ground where a deer that died with chronic wasting disease
Chronic wasting disease (CWD), sometimes called zombie deer disease, is a transmissible spongiform encephalopathy (TSE) affecting deer. TSEs are a family of diseases thought to be caused by misfolded proteins called prions and include similar dis ...
(CWD) was buried, the hamsters became ill with CWD, suggesting that prions can bind to plants, which then take them up into the leaf and stem structure, where they can be eaten by herbivores, thus completing the cycle. It is thus possible that there is a progressively accumulating number of prions in the environment.
Sterilization
Infectious particles possessing nucleic acid
Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...
are dependent upon it to direct their continued replication. Prions, however, are infectious by their effect on normal versions of the protein. Sterilizing prions, therefore, requires the denaturation of the protein to a state in which the molecule is no longer able to induce the abnormal folding of normal proteins. In general, prions are quite resistant to protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
s, heat, ionizing radiation
Ionizing radiation (or ionising radiation), including nuclear radiation, consists of subatomic particles or electromagnetic waves that have sufficient energy to ionize atoms or molecules by detaching electrons from them. Some particles can travel ...
, and formaldehyde
Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section F ...
treatments, although their infectivity can be reduced by such treatments. Effective prion decontamination relies upon protein hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
or reduction or destruction of protein tertiary structure
Protein tertiary structure is the three dimensional shape of a protein. The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures, the protein domains. Amino acid side chains may inter ...
. Examples include sodium hypochlorite
Sodium hypochlorite (commonly known in a dilute solution as bleach) is an Inorganic chemistry, inorganic chemical compound with the chemical formula, formula NaOCl (or NaClO), comprising a sodium cation () and a hypochlorite anion (or ). It may ...
, sodium hydroxide
Sodium hydroxide, also known as lye and caustic soda, is an inorganic compound with the formula NaOH. It is a white solid ionic compound consisting of sodium cations and hydroxide anions .
Sodium hydroxide is a highly caustic base and alkali ...
, and strongly acidic detergent
A detergent is a surfactant or a mixture of surfactants with cleansing properties when in dilute solutions. There are a large variety of detergents, a common family being the alkylbenzene sulfonates, which are soap-like compounds that are more ...
s such as LpH.
The World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
recommends any of the following three procedures for the sterilization of all heat-resistant surgical instruments to ensure that they are not contaminated with prions:
# Immerse in 1N sodium hydroxide and place in a gravity-displacement autoclave at 121 °C for 30 minutes; clean; rinse in water; and then perform routine sterilization processes.
# Immerse in 1N sodium hypochlorite (20,000 parts per million available chlorine) for 1 hour; transfer instruments to water; heat in a gravity-displacement autoclave at 121 °C for 1 hour; clean; and then perform routine sterilization processes.
# Immerse in 1N sodium hydroxide or sodium hypochlorite (20,000 parts per million available chlorine) for 1 hour; remove and rinse in water, then transfer to an open pan and heat in a gravity-displacement (121 °C) or in a porous-load (134 °C) autoclave for 1 hour; clean; and then perform routine sterilization processes.
for 18 minutes in a pressurized steam autoclave
An autoclave is a machine used to carry out industrial and scientific processes requiring elevated temperature and pressure in relation to ambient pressure and/or temperature. Autoclaves are used before surgical procedures to perform sterilizat ...
has been found to be somewhat effective in deactivating the agent of disease. Ozone
Ozone (), or trioxygen, is an inorganic molecule with the chemical formula . It is a pale blue gas with a distinctively pungent smell. It is an allotrope of oxygen that is much less stable than the diatomic allotrope , breaking down in the lo ...
sterilization is currently being studied as a potential method for prion denaturation and deactivation. Other approaches being developed include thiourea
Thiourea () is an organosulfur compound with the formula and the structure . It is structurally similar to urea (), except that the oxygen atom is replaced by a sulfur atom (as implied by the ''thio-'' prefix); however, the properties of urea ...
-urea
Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid.
Urea serves an important r ...
treatment, guanidinium chloride
Guanidinium chloride or guanidine hydrochloride, usually abbreviated GdmCl and sometimes GdnHCl or GuHCl, is the hydrochloride salt of guanidine.
Structure
Guanidinium chloride crystallizes in orthorhombic space group ''Pbca''. The crystal stru ...
treatment, and special heat-resistant subtilisin
Subtilisin is a protease (a protein-digesting enzyme) initially obtained from ''Bacillus subtilis''.
Subtilisins belong to subtilases, a group of serine proteases that – like all serine proteases – initiate the nucleophilic attack on the p ...
combined with heat and detergent. A method sufficient for sterilizing prions on one material may fail on another.
Renaturation of a completely denatured prion to infectious status has not yet been achieved; however, partially denatured prions can be renatured to an infective status under certain artificial conditions.
Degradation resistance in nature
Overwhelming evidence shows that prions resist degradation and persist in the environment for years, and protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
s do not degrade them. Experimental evidence shows that ''unbound'' prions degrade over time, while soil-bound prions remain at stable or increasing levels, suggesting that prions likely accumulate in the environment. One 2015 study by US scientists found that repeated drying and wetting may render soil bound prions less infectious, although this was dependent on the soil type they were bound to.
Fungi
Proteins showing prion-type behavior are also found in some fungi
A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...
, which has been useful in helping to understand mammalian prions. Fungal prion
A fungal prion is a prion that infects fungal hosts. Fungal prions are naturally occurring proteins that can switch between multiple, structurally distinct conformations, at least one of which is self-propagating and transmissible to other prion ...
s do not appear to cause disease in their hosts. In yeast, protein refolding to the prion configuration is assisted by chaperone proteins such as Hsp104 Hsp104 is a heat-shock protein. It is known to reverse toxicity of mutant α-synuclein, TDP-43, FUS, and TAF15 in yeast
Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast origin ...
. All known prions induce the formation of an amyloid
Amyloids are aggregates of proteins characterised by a Fibril, fibrillar morphology of 7–13 Nanometer, nm in diameter, a beta sheet (β-sheet) Secondary structure of proteins, secondary structure (known as cross-β) and ability to be Staining, ...
fold, in which the protein polymerises into an aggregate consisting of tightly packed beta sheet
The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a g ...
s. Amyloid aggregates are fibrils, growing at their ends, and replicate when breakage causes two growing ends to become four growing ends. The incubation period
Incubation period (also known as the latent period or latency period) is the time elapsed between exposure to a pathogenic organism, a chemical, or radiation, and when symptoms and signs are first apparent. In a typical infectious disease, the i ...
of prion diseases is determined by the exponential growth
Exponential growth is a process that increases quantity over time. It occurs when the instantaneous rate of change (that is, the derivative) of a quantity with respect to time is proportional to the quantity itself. Described as a function, a q ...
rate associated with prion replication, which is a balance between the linear growth and the breakage of aggregates.
Fungal proteins exhibiting templated conformational change were discovered in the yeast ''Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...
'' by Reed Wickner
Reed B. Wickner (born c. 1942) is an American yeast geneticist. In 1994 he proposed that the 'PSI''+and RE3phenotypes in ''Saccharomyces cerevisiae'', a form of budding yeast, were caused by prion forms of native proteins - specifically, the Su ...
in the early 1990s. For their mechanistic similarity to mammalian prions, they were termed yeast prion
A fungal prion is a prion that infects fungal hosts. Fungal prions are naturally occurring proteins that can switch between multiple, structurally distinct conformations, at least one of which is self-propagating and transmissible to other prion ...
s. Subsequent to this, a prion has also been found in the fungus ''Podospora anserina
''Podospora anserina'' is a filamentous ascomycete fungus from the order Sordariales. It is considered a model organism for the study of molecular biology of senescence (aging), prions, sexual reproduction, and meiotic drive. It has an obligat ...
''. These prions behave similarly to PrP, but, in general, are nontoxic to their hosts. Susan Lindquist
Susan Lee Lindquist, ForMemRS (June 5, 1949 – October 27, 2016) was an American professor of biology at MIT specializing in molecular biology, particularly the protein folding problem within a family of molecules known as heat-shock proteins ...
's group at the Whitehead Institute
Whitehead Institute for Biomedical Research is a non-profit research institute located in Cambridge, Massachusetts, United States that is dedicated to improving human health through basic biomedical research. It was founded as a fiscally indepen ...
has argued some of the fungal prions are not associated with any disease state, but may have a useful role; however, researchers at the NIH have also provided arguments suggesting that fungal prions could be considered a diseased state. There is evidence that fungal proteins have evolved specific functions that are beneficial to the microorganism that enhance their ability to adapt to their diverse environments.
Research into fungal prion
A fungal prion is a prion that infects fungal hosts. Fungal prions are naturally occurring proteins that can switch between multiple, structurally distinct conformations, at least one of which is self-propagating and transmissible to other prion ...
s has given strong support to the protein-only concept, since purified protein extracted from cells with a prion state has been demonstrated to convert the normal form of the protein into a misfolded form ''in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'', and in the process, preserve the information corresponding to different strains of the prion state. It has also shed some light on prion domains, which are regions in a protein that promote the conversion into a prion. Fungal prions have helped to suggest mechanisms of conversion that may apply to all prions, though fungal prions appear distinct from infectious mammalian prions in the lack of cofactor required for propagation. The characteristic prion domains may vary between species – e.g., characteristic fungal prion domains are not found in mammalian prions.
Treatments
There are no effective treatments for prion diseases. Clinical trials in humans have not met with success and have been hampered by the rarity of prion diseases. Although some potential treatments have shown promise in the laboratory, none have been effective once the disease has commenced.
In other diseases
Prion-like domains have been found in a variety of other mammalian proteins. Some of these proteins have been implicated in the ontogeny of age-related neurodegenerative disorders such as amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
(ALS), frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
, Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
, and Huntington's disease
Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unst ...
. They are also implicated in some forms of systemic amyloidosis
Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weight ...
including AA amyloidosis
AA amyloidosis is a form of amyloidosis, a disease characterized by the abnormal deposition of fibers of insoluble protein in the extracellular space of various tissues and organs. In AA amyloidosis, the deposited protein is serum amyloid A protein ...
that develops in humans and animals with inflammatory and infectious diseases such as tuberculosis
Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in ...
, Crohn's disease
Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension ...
, rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
, and HIV/AIDS
Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...
. AA amyloidosis, like prion disease, may be transmissible. This has given rise to the 'prion paradigm', where otherwise harmless proteins can be converted to a pathogenic form by a small number of misfolded, nucleating proteins.
The definition of a prion-like domain arises from the study of fungal prions. In yeast, prionogenic proteins have a portable prion domain that is both necessary and sufficient for self-templating and protein aggregation. This has been shown by attaching the prion domain to a reporter protein, which then aggregates like a known prion. Similarly, removing the prion domain from a fungal prion protein inhibits prionogenesis. This modular view of prion behaviour has led to the hypothesis that similar prion domains are present in animal proteins, in addition to PrP. These fungal prion domains have several characteristic sequence features. They are typically enriched in asparagine, glutamine, tyrosine and glycine residues, with an asparagine bias being particularly conducive to the aggregative property of prions. Historically, prionogenesis has been seen as independent of sequence and only dependent on relative residue content. However, this has been shown to be false, with the spacing of prolines and charged residues having been shown to be critical in amyloid formation.
Bioinformatic screens have predicted that over 250 human proteins contain prion-like domains (PrLD). These domains are hypothesized to have the same transmissible, amyloidogenic properties of PrP and known fungal proteins. As in yeast, proteins involved in gene expression and RNA binding seem to be particularly enriched in PrLD's, compared to other classes of protein. In particular, 29 of the known 210 proteins with an RNA recognition motif also have a putative prion domain. Meanwhile, several of these RNA-binding proteins have been independently identified as pathogenic in cases of ALS, FTLD-U, Alzheimer's disease, and Huntington's disease.
Role in neurodegenerative disease
The pathogenicity of prions and proteins with prion-like domains is hypothesized to arise from their self-templating ability and the resulting exponential growth of amyloid fibrils. The presence of amyloid
Amyloids are aggregates of proteins characterised by a Fibril, fibrillar morphology of 7–13 Nanometer, nm in diameter, a beta sheet (β-sheet) Secondary structure of proteins, secondary structure (known as cross-β) and ability to be Staining, ...
fibrils in patients with degenerative diseases has been well documented. These amyloid fibrils are seen as the result of pathogenic proteins that self-propagate and form highly stable, non-functional aggregates. While this does not necessarily imply a causal relationship between amyloid and degenerative diseases, the toxicity of certain amyloid forms and the overproduction of amyloid in familial cases of degenerative disorders supports the idea that amyloid formation is generally toxic.
Specifically, aggregation of TDP-43
TAR DNA-binding protein 43 (TDP-43, transactive response DNA binding protein 43 kDa) is a protein that in humans is encoded by the ''TARDBP'' gene.
Structure
TDP-43 is 414 amino acid residues long. It consists of 4 domains: an N-terminal d ...
, an RNA-binding protein, has been found in ALS/MND patients, and mutations in the genes coding for these proteins have been identified in familial cases of ALS/MND. These mutations promote the misfolding of the proteins into a prion-like conformation. The misfolded form of TDP-43 forms cytoplasmic inclusions in affected neurons, and is found depleted in the nucleus. In addition to ALS/MND and FTLD-U, TDP-43 pathology is a feature of many cases of Alzheimer's disease, Parkinson's disease and Huntington's disease. The misfolding of TDP-43 is largely directed by its prion-like domain. This domain is inherently prone to misfolding, while pathological mutations in TDP-43 have been found to increase this propensity to misfold, explaining the presence of these mutations in familial cases of ALS/MND. As in yeast, the prion-like domain of TDP-43 has been shown to be both necessary and sufficient for protein misfolding and aggregation.
Similarly, pathogenic mutations have been identified in the prion-like domains of heterogeneous nuclear riboproteins hnRNPA2B1 and hnRNPA1 in familial cases of muscle, brain, bone and motor neuron degeneration. The wild-type form of all of these proteins show a tendency to self-assemble into amyloid fibrils, while the pathogenic mutations exacerbate this behaviour and lead to excess accumulation.
Weaponization
Prions could theoretically be employed as a weaponized agent. With potential fatality rates of 100%, prions could be an effective bio-weapon. An unfavorable aspect is prions' very long incubation periods. Persistent heavy exposure of prions to the intestine
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans ...
might shorten the overall onset. Another aspect of using prions in warfare is the difficulty of detection and decontamination
Decontamination (sometimes abbreviated as decon, dcon, or decontam) is the process of removing contaminants on an object or area, including chemicals, micro-organisms or radioactive substances. This may be achieved by chemical reaction, disinfecti ...
.
History
In the 18th and 19th centuries, exportation of sheep from Spain was observed to coincide with a disease called scrapie
Scrapie () is a fatal, degenerative disease affecting the nervous systems of sheep and goats. It is one of several transmissible spongiform encephalopathies (TSEs), and as such it is thought to be caused by a prion. Scrapie has been known since ...
. This disease caused the affected animals to ''"lie down, bite at their feet and legs, rub their backs against posts, fail to thrive, stop feeding and finally become lame"''. The disease was also observed to have the long incubation period that is a key characteristic of transmissible spongiform encephalopathies (TSEs). Although the cause of scrapie was not known back then, it is probably the first transmissible spongiform encephalopathy to be recorded.
In the 1950s, Carleton Gajdusek began research which eventually showed that kuru
Kuru may refer to:
Anthropology and history
* Kuru (disease), a type of transmissible spongiform encephalopathy associated with the cannibalistic funeral practices of the Fore people
* Kuru (mythology), part of Meithei mythology
* Kuru Kingdom, ...
could be transmitted to chimpanzees by what was possibly a new infectious agent, work for which he eventually won the 1976 Nobel prize
The Nobel Prizes ( ; sv, Nobelpriset ; no, Nobelprisen ) are five separate prizes that, according to Alfred Nobel's will of 1895, are awarded to "those who, during the preceding year, have conferred the greatest benefit to humankind." Alfr ...
. During the 1960s, two London-based researchers, radiation biologist Tikvah Alper
Tikvah Alper (22 January 1909 – 2 February 1995) trained as a physicist and became a distinguished radiobiologist. Among many other initiatives and discoveries, she was among the first to find evidence indicating that the infectious agent in ...
and biophysicist John Stanley Griffith
John Stanley Griffith (1928–1972) was a British chemist, mathematician and biophysicist. He was the nephew of the distinguished British bacteriologist Frederick Griffith.
Career
Beginning as an undergraduate in mathematics at Trinity College ...
, developed the hypothesis that the transmissible spongiform encephalopathies
Transmissible spongiform encephalopathies (TSEs) are a group of progressive and fatal conditions that are associated with prions and affect the brain and nervous system of many animals, including humans, cattle, and sheep. According to the most ...
are caused by an infectious agent consisting solely of proteins. Earlier investigations by E.J. Field
Ephraim Joshua Field (20 March 1915 – 1 August 2002) was a British neuroscientist.
Education
Field studied Medicine at the University of Durham, UK. Previously Lecturer and then Reader in Anatomy at the University of Bristol, he moved to Newca ...
into scrapie
Scrapie () is a fatal, degenerative disease affecting the nervous systems of sheep and goats. It is one of several transmissible spongiform encephalopathies (TSEs), and as such it is thought to be caused by a prion. Scrapie has been known since ...
and kuru had found evidence for the transfer of pathologically inert polysaccharides that only become infectious post-transfer, in the new host. Alper and Griffith wanted to account for the discovery that the mysterious infectious agent causing the diseases scrapie and Creutzfeldt–Jakob disease
Creutzfeldt–Jakob disease (CJD), also known as subacute spongiform encephalopathy or neurocognitive disorder due to prion disease, is an invariably fatal degenerative brain disorder. Early symptoms include memory problems, behavioral changes, ...
resisted ionizing radiation
Ionizing radiation (or ionising radiation), including nuclear radiation, consists of subatomic particles or electromagnetic waves that have sufficient energy to ionize atoms or molecules by detaching electrons from them. Some particles can travel ...
. Griffith proposed three ways in which a protein could be a pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
.
In the first hypothesis
A hypothesis (plural hypotheses) is a proposed explanation for a phenomenon. For a hypothesis to be a scientific hypothesis, the scientific method requires that one can test it. Scientists generally base scientific hypotheses on previous obse ...
, he suggested that if the protein is the product of a normally suppressed gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
, and introducing the protein could induce the gene's expression, that is, wake the dormant gene up, then the result would be a process indistinguishable from replication, as the gene's expression would produce the protein, which would then go wake the gene up in other cells.
His second hypothesis forms the basis of the modern prion theory, and proposed that an abnormal form of a cellular protein can convert normal proteins of the same type into its abnormal form, thus leading to replication.
His third hypothesis proposed that the agent could be an antibody
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
if the antibody was its own target antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
, as such an antibody would result in more and more antibody being produced against itself. However, Griffith acknowledged that this third hypothesis was unlikely to be true due to the lack of a detectable immune response
An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...
.
Francis Crick
Francis Harry Compton Crick (8 June 1916 – 28 July 2004) was an English molecular biologist, biophysicist, and neuroscientist. He, James Watson, Rosalind Franklin, and Maurice Wilkins played crucial roles in deciphering the helical struc ...
recognized the potential significance of the Griffith protein-only hypothesis for scrapie propagation in the second edition of his "Central dogma of molecular biology
The central dogma of molecular biology is an explanation of the flow of genetic information within a biological system. It is often stated as "DNA makes RNA, and RNA makes protein", although this is not its original meaning. It was first stated by ...
" (1970): While asserting that the flow of sequence information from protein to protein, or from protein to RNA and DNA was "precluded", he noted that Griffith's hypothesis was a potential contradiction (although it was not so promoted by Griffith). The revised hypothesis was later formulated, in part, to accommodate reverse transcription (which both Howard Temin
Howard Martin Temin (December 10, 1934 – February 9, 1994) was an American geneticist and virologist. He discovered reverse transcriptase in the 1970s at the University of Wisconsin–Madison, for which he shared the 1975 Nobel Prize in Phy ...
and David Baltimore
David Baltimore (born March 7, 1938) is an American biologist, university administrator, and 1975 Nobel laureate in Physiology or Medicine. He is President Emeritus and Distinguished Professor of Biology at the California Institute of Technolo ...
discovered in 1970).
In 1982, Stanley B. Prusiner of the University of California, San Francisco
The University of California, San Francisco (UCSF) is a public land-grant research university in San Francisco, California. It is part of the University of California system and is dedicated entirely to health science and life science. It cond ...
, announced that his team had purified the hypothetical infectious protein, which did not appear to be present in healthy hosts, though they did not manage to isolate the protein until two years after Prusiner's announcement. The protein was named a prion, for "proteinacious infectious particle", derived from the words protein and infection. When the prion was discovered, Griffith's first hypothesis, that the protein was the product of a normally silent gene was favored by many. It was subsequently discovered, however, that the same protein exists in normal hosts but in different form.
Following the discovery of the same protein in different form in uninfected individuals, the specific protein that the prion was composed of was named the prion protein (PrP), and Griffith's second hypothesis that an abnormal form of a host protein can convert other proteins of the same type into its abnormal form, became the dominant theory. Prusiner won the Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
in 1997 for his research into prions.
See also
* Diseases of abnormal polymerization
* Prion pseudoknot
* Subviral agents
Virus classification is the process of naming viruses and placing them into a taxonomic system similar to the classification systems used for cellular organisms.
Viruses are classified by phenotypic characteristics, such as morphology, nucleic ...
* Tau protein
The tau proteins (abbreviated from tubulin associated unit) are a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintaining ...
References
External links
CDC
– US Center for Disease Control and Prevention – information on prion diseases
World Health Organisation
– WHO information on prion diseases
The UK BSE Inquiry
nbsp;– Report of the UK public inquiry into BSE and variant CJD
UK Spongiform Encephalopathy Advisory Committee (SEAC)
{{Authority control
Amyloidosis
Genetics
Proteins