PRNP
Encyclopedia
Major prion protein also known as CD230 (cluster of differentiation
230) is a protein
that in humans is encoded by the PRNP gene
(PRioN Protein (Creutzfeld-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome
, fatal familial insomnia
)). The major prion protein is expressed in the brain
and several other tissues.
Expression is most predominant in the nervous system
but occurs in many other tissues throughout the body. Human PrP is associated with a variety of cognitive deficiencies and neurodegenerative diseases such as Creutzfeld-Jakob disease, bovine spongiform encephalopathy
, and kuru (disease)
.
between the end (terminus) of the arm and position 12, from base pair
4,615,068 to base pair 4,630,233.
Two distinct major conformational forms of PrP have been identified in the nervous system
. The usual cellular form is denoted PrPC (for cellular or common form). Another form, PrPSc (for scrapie), has an identical amino acid sequence, but is folded into a different shape or conformation. The PrPSc form is associated with a number of degenerative disorders of the brain and nervous system. In a process that is not fully understood, PrPC is occasionally transformed into the infectious isomer PrPSc. This abnormal protein can further promote the transformation of PrPC into PrPSc, leading to transmissible spongiform encephalopathy
.
The primary sequence of PrP is 253 amino acid
s long before posttranslational modification
. Signal sequence
s in the amino
- and carboxy- terminal ends which are removed posttranslationally. For human
and Syrian hamster PrP, two glycosylated sites exist on helices 2 and 3 at Asn
181 and Asn197. Murine PrP has glycosylation sites as Asn180 and Asn196. A disulfide bond
exists between Cys
179 of the second helix and Cys214 of the third helix (human PrPC numbering).
PrP messenger RNA
contains a pseudoknot
structure (prion pseudoknot
) which is thought to be involved in regulation of PrP protein translation.
PrPSC is a conformational isomer of PrPC , but this orientation tends to accumulate in compact, protease
-resistant aggregates within neural tissue. The propagation of PrPSC is a topic of great interest, as it’s accumulation is the pathological cause of neurodegeneration
. Based on the progressive natural of spongiform encephalopathies, the predominant hypothesis posits that the change from normal PrPC is caused by the presence and interaction with PrPSC. Strong support for this is taken from studies in which PRNP-knockout mice are resistant to the introduction of PrPSC. Despite widespread acceptance of the conformation conversion hypothesis, some studies mitigate claims for a direct link between PrPSC and cytotoxicity.
-protein, but so far, no such compound have been identified. However, a large body of research has developed on candidates and their interaction with the PrPC. Presently, copper
is the only confirmed ligand, though the implication of this knowledge are a matter of much debate; the NH2-tail region has been shown to bind Cu2+. The binding caused a conformational change, with unknown effect. The copper-PrP interaction has been linked to resistance to oxidative stress
.
ic copper to cells from the surrounding environment. Researchers have also proposed roles for PrP in cell signaling or in the formation of synapse
s . PrPC attaches to the outer surface of the cell membrane
by a glycosylphosphatidylinositol anchor at its C-terminal Ser
231.
Prion protein contains 5 amino-terminal octapeptide
repeats with sequence PHGGGWGQ. This is thought to generate a calcium
binding domain
via nitrogen atoms in the histidine
imidazole
side chain
s and deprotonated amide
nitrogens from the 2nd and 3rd glycines in the repeat. The ability to bind calcium is therefore pH
dependent. NMR
shows calcium binding results in a conformational
change at the N-terminus.
and tertiary structure
from PrPC, but identical primary sequence. Circular dichroism
shows that normal PrPC had 43% alpha helical
and 3% beta sheet
content, whilst PrPSc was only 30% alpha helix and 43% beta sheet. This refolding renders the PrPSc isoform extremely resistant to proteolysis
.
Polymorphisms
at sites 136, 154 and 171 are associated with varying susceptibility to scrapie
. Polymorphisms of the PrP-VRQ form and PrP-ARQ form are associated with increased susceptibility, whilst PrP-ARR is associated with resistance.
The National Scrapie Plan aims to breed out these scrapie polymorphisms by increasing the frequency of the resistant allele. However, PrP-ARR polymorphisms are susceptible to atypical scrapie so this may prove unfruitful.
As the null mice age, a marked loss of Purkinje cells in the cerebellum
results in decreased motor coordination. However, this effect is not a direct result of PrP’s absence, and rather arises from increased Doppel gene expression. Other observed differences include reduced stress response and increased exploration of novel environments.
Circadian rhythm
is altered in null mice. Fatal familial insomnia
is thought to be the result of a point mutation in PRNP at codon 178, which corroborates PrP’s involvement in sleep-wake cycles. In addition, circadian regulation has been demonstrated in PrP mRNA, which cycles regularly with day-night.
, long-term memory
consolidation deficits have been demonstrated. Like ataxia
, though, this is attributable to Doppel gene expression. However, spatial learning, a predominantly hippocampal-function, is decreased in the null mice and can be recovered with the reinstatement of PrP in neurons; this indicates that loss of PrP function is the cause. The interaction of hippocampal PrP with laminin
(LN) is pivotal in memory processing and is likely modulated by the kinases PKA and ERK1/2.
Further support for PrP’s role in memory formation is derived from several population studies. A test of healthy young humans showed increased long-term memory ability associated with an MM or MV genotype when compared to VV. Down Syndrome
patients with a single valine
substitution have been linked to earlier cognitive decline. Several polymorphisms in PRNP have been linked with cognitive impairment in the elderly as well as earlier cognitive decline. All of these studies investigated differences in codon 129, indicating its importance in the overall functionality of PrP, particularly in regard to memory.
mechanism, a calcium modulator, or a sensory for copper or oxidative stress. Loss of PrP function has been linked to long-term potentiation
(LTP). This effect can be positive or negative and is due to changes in neuronal excitability and synaptic transmission in the hippocampus
.
Some research indicates PrP involvement in neuronal development, differentiation, and neurite
outgrowth. The PrP-activated signal transduction pathway is associated with axon and dendritic outgrowth with a series of kinases.
activation is accompanied by a strong up-regulation of PrP, though it is not requisite. The lack of immuno-response to transmissible spongiform encephalopathy
(TSE), neurdegenerative diseases caused by prions, could stem from the tolerance for PrPSC.
Though present, very low levels of PrP exist in the liver and could to be associated with liver fibrosis. Presence in the pituitary has been shown to affect neuroendrocrine function in amphibians, but little is known concerning mammalian pituitary PrP.
Some PRNP mutations lead to a change in single amino acid
s (the building blocks of proteins) in the prion protein. Others insert additional amino acids into the protein or cause an abnormally short protein to be made. These mutations cause the cell to make prion proteins with an abnormal structure. The abnormal protein, PrPSc, accumulates in the brain and destroys nerve cells, which leads to the mental and behavioral features of prion diseases.
Several other changes in the PRNP gene (called polymorphisms) do not cause prion diseases, but may affect a person's risk of developing these diseases or alter the course of the disorders. An allele
which codes for a PRNP variant — G127V provides resistance to Kuru
.
The conversion of PrPC to PrPSC conformation is the mechanism of transmission of fatal, neurodegenerative transmissible spongiform encephalopathies (TSE). This can arise from genetic factors, infection from external source, or spontaneously for reasons unknown. Accumulation of PrPSC corresponds with progression of neurodegeneration and is the proposed cause.
A variety of mutations in the PRNP gene have resulted in inherited prion diseases.
Additionally, some prion diseases can be transmitted from external sources of PrPSC.
with Hop
.
A strong interaction exists between PrP and cochaperone Hsp70
/Hsp90
organizing protein/Stress-induced protein 1 (hop (protein)
/STI1).
Cluster of differentiation
The cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on white blood cells, providing targets for immunophenotyping of cells...
230) is a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the PRNP gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
(PRioN Protein (Creutzfeld-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome
Gerstmann-Sträussler-Scheinker syndrome
Gerstmann–Sträussler–Scheinker syndrome is a very rare, usually familial, fatal neurodegenerative disease that affects patients from 20 to 60 years in age...
, fatal familial insomnia
Fatal familial insomnia
Fatal familial insomnia is a very rare autosomal dominant inherited prion disease of the brain. It is almost always caused by a mutation to the protein PrPC, but can also develop spontaneously in patients with a non-inherited mutation variant called sporadic fatal insomnia...
)). The major prion protein is expressed in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
and several other tissues.
Expression is most predominant in the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
but occurs in many other tissues throughout the body. Human PrP is associated with a variety of cognitive deficiencies and neurodegenerative diseases such as Creutzfeld-Jakob disease, bovine spongiform encephalopathy
Bovine spongiform encephalopathy
Bovine spongiform encephalopathy , commonly known as mad-cow disease, is a fatal neurodegenerative disease in cattle that causes a spongy degeneration in the brain and spinal cord. BSE has a long incubation period, about 30 months to 8 years, usually affecting adult cattle at a peak age onset of...
, and kuru (disease)
Kuru (disease)
Kuru is an incurable degenerative neurological disorder that is a type of transmissible spongiform encephalopathy, caused by a prion found in humans...
.
Gene
The human PRNP gene is located on the short (p) arm of chromosome 20Chromosome 20 (human)
Chromosome 20 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 20 spans around 63 million base pairs and represents between 2 and 2.5 percent of the total DNA in cells...
between the end (terminus) of the arm and position 12, from base pair
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
4,615,068 to base pair 4,630,233.
Structure
PrP is highly conserved through mammals, lending credence to application of conclusions from test animals such as mice. Comparison between primates is especially similar, ranging from 92.9-99.6% similarity in amino acid sequences. The human protein structure consists of a globular domain with three α-helices and a two-stranded antiparallel β-sheet, an NH2-terminal tail, and a short COOH-terminal tail. A glycosylphosphatidylinositol (GPI) membrane anchor at the COOH-terminal tethers PrP to cell membranes, and this proves to be integral to the transmission of conformation change; secreted PrP lacking the anchor component is unaffected by the infectious isoform.Two distinct major conformational forms of PrP have been identified in the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
. The usual cellular form is denoted PrPC (for cellular or common form). Another form, PrPSc (for scrapie), has an identical amino acid sequence, but is folded into a different shape or conformation. The PrPSc form is associated with a number of degenerative disorders of the brain and nervous system. In a process that is not fully understood, PrPC is occasionally transformed into the infectious isomer PrPSc. This abnormal protein can further promote the transformation of PrPC into PrPSc, leading to transmissible spongiform encephalopathy
Transmissible spongiform encephalopathy
Transmissible spongiform encephalopathies , also known as prion diseases, are a group of progressive conditions that affect the brain and nervous system of many animals, including humans. According to the most widespread hypothesis they are transmitted by prions, though some other data suggest an...
.
The primary sequence of PrP is 253 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s long before posttranslational modification
Posttranslational modification
Posttranslational modification is the chemical modification of a protein after its translation. It is one of the later steps in protein biosynthesis, and thus gene expression, for many proteins....
. Signal sequence
Signal sequence
Signal sequence can refer to:*Protein targeting*Signal peptide*DNA uptake signal sequence...
s in the amino
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
- and carboxy- terminal ends which are removed posttranslationally. For human
Human
Humans are the only living species in the Homo genus...
and Syrian hamster PrP, two glycosylated sites exist on helices 2 and 3 at Asn
ASN
ASN may refer to:Organisations:* ASN Bank in the Netherlands* American Society of Nephrology* American Society for Neurochemistry* American Society of Neuroimaging* American Society for Nutrition...
181 and Asn197. Murine PrP has glycosylation sites as Asn180 and Asn196. A disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
exists between Cys
CYS
CYS may refer to:* Cysteine an amino-acid* IATA airport code for Cheyenne Regional Airport.* California Youth Symphony, a San Francisco Bay Area symphony orchestra for young musicians* Count Your Sheep, a webcomic by Adrian Ramos...
179 of the second helix and Cys214 of the third helix (human PrPC numbering).
PrP messenger RNA
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
contains a pseudoknot
Pseudoknot
A pseudoknot is a nucleic acid secondary structure containing at least two stem-loop structures in which half of one stem is intercalated between the two halves of another stem. The pseudoknot was first recognized in the turnip yellow mosaic virus in 1982...
structure (prion pseudoknot
Prion pseudoknot
The prion pseudoknot is predicted RNA pseudoknot structure found in prion protein mRNA. It has been suggested that this element has a possible effect in prion protein translation. The human prion protein contains 5 copies of a 24 nucleotide repeat that contains this structure....
) which is thought to be involved in regulation of PrP protein translation.
Conformations
The functional conformation, PrPC, is observed in the nervous system.PrPSC is a conformational isomer of PrPC , but this orientation tends to accumulate in compact, protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
-resistant aggregates within neural tissue. The propagation of PrPSC is a topic of great interest, as it’s accumulation is the pathological cause of neurodegeneration
Neurodegeneration
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...
. Based on the progressive natural of spongiform encephalopathies, the predominant hypothesis posits that the change from normal PrPC is caused by the presence and interaction with PrPSC. Strong support for this is taken from studies in which PRNP-knockout mice are resistant to the introduction of PrPSC. Despite widespread acceptance of the conformation conversion hypothesis, some studies mitigate claims for a direct link between PrPSC and cytotoxicity.
Ligand-binding
The mechanism for conformational conversion is speculated to be an elusive ligandLigand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
-protein, but so far, no such compound have been identified. However, a large body of research has developed on candidates and their interaction with the PrPC. Presently, copper
Copper
Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...
is the only confirmed ligand, though the implication of this knowledge are a matter of much debate; the NH2-tail region has been shown to bind Cu2+. The binding caused a conformational change, with unknown effect. The copper-PrP interaction has been linked to resistance to oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
.
PrPC (normal cellular) isoform
Although the precise function of PrP is not yet known, it is possibly involved in the transport of ionIon
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
ic copper to cells from the surrounding environment. Researchers have also proposed roles for PrP in cell signaling or in the formation of synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
s . PrPC attaches to the outer surface of the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
by a glycosylphosphatidylinositol anchor at its C-terminal Ser
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
231.
Prion protein contains 5 amino-terminal octapeptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
repeats with sequence PHGGGWGQ. This is thought to generate a calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
binding domain
Binding domain
A binding domain is a protein domain which binds to a specific atom or molecule, such as calcium or DNA. Upon binding, proteins may undergo a conformational change. Binding domains are essential for the function of many proteins....
via nitrogen atoms in the histidine
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
imidazole
Imidazole
Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents...
side chain
Side chain
In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called "main chain" or backbone. The placeholder R is often used as a generic placeholder for alkyl group side chains in chemical structure diagrams. To indicate other non-carbon...
s and deprotonated amide
Amide
In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
nitrogens from the 2nd and 3rd glycines in the repeat. The ability to bind calcium is therefore pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
dependent. NMR
Nuclear magnetic resonance
Nuclear magnetic resonance is a physical phenomenon in which magnetic nuclei in a magnetic field absorb and re-emit electromagnetic radiation...
shows calcium binding results in a conformational
Protein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
change at the N-terminus.
PrPSc (scrapie) isoform
The abnormal PrPSc isoform has a different secondarySecondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
and tertiary structure
Tertiary structure
In biochemistry and molecular biology, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates.-Relationship to primary structure:...
from PrPC, but identical primary sequence. Circular dichroism
Circular dichroism
Circular dichroism refers to the differential absorption of left and right circularly polarized light. This phenomenon was discovered by Jean-Baptiste Biot, Augustin Fresnel, and Aimé Cotton in the first half of the 19th century. It is exhibited in the absorption bands of optically active chiral...
shows that normal PrPC had 43% alpha helical
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
and 3% beta sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
content, whilst PrPSc was only 30% alpha helix and 43% beta sheet. This refolding renders the PrPSc isoform extremely resistant to proteolysis
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
.
Polymorphisms
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
at sites 136, 154 and 171 are associated with varying susceptibility to scrapie
Scrapie
Scrapie is a fatal, degenerative disease that affects the nervous systems of sheep and goats. It is one of several transmissible spongiform encephalopathies , which are related to bovine spongiform encephalopathy and chronic wasting disease of deer. Like other spongiform encephalopathies, scrapie...
. Polymorphisms of the PrP-VRQ form and PrP-ARQ form are associated with increased susceptibility, whilst PrP-ARR is associated with resistance.
The National Scrapie Plan aims to breed out these scrapie polymorphisms by increasing the frequency of the resistant allele. However, PrP-ARR polymorphisms are susceptible to atypical scrapie so this may prove unfruitful.
Nervous system
The strong association to neurodegenerative diseases raises many questions of the function of PrP in the brain. A common approach is using PrP-knockout and transgenic mice investigate deficiencies and differences. Initial attempts produced two strains of PrP-null mice that shows no physiological or developmental differences when subjects to an array of tests. However, more recent strains have shown significant cognitive abnormalities.As the null mice age, a marked loss of Purkinje cells in the cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
results in decreased motor coordination. However, this effect is not a direct result of PrP’s absence, and rather arises from increased Doppel gene expression. Other observed differences include reduced stress response and increased exploration of novel environments.
Circadian rhythm
Circadian rhythm
A circadian rhythm, popularly referred to as body clock, is an endogenously driven , roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria...
is altered in null mice. Fatal familial insomnia
Fatal familial insomnia
Fatal familial insomnia is a very rare autosomal dominant inherited prion disease of the brain. It is almost always caused by a mutation to the protein PrPC, but can also develop spontaneously in patients with a non-inherited mutation variant called sporadic fatal insomnia...
is thought to be the result of a point mutation in PRNP at codon 178, which corroborates PrP’s involvement in sleep-wake cycles. In addition, circadian regulation has been demonstrated in PrP mRNA, which cycles regularly with day-night.
Memory
While null mice exhibit normal learning ability and short-term memoryShort-term memory
Short-term memory is the capacity for holding a small amount of information in mind in an active, readily available state for a short period of time. The duration of short-term memory is believed to be in the order of seconds. A commonly cited capacity is 7 ± 2 elements...
, long-term memory
Long-term memory
Long-term memory is memory in which associations among items are stored, as part of the theory of a dual-store memory model. According to the theory, long term memory differs structurally and functionally from working memory or short-term memory, which ostensibly stores items for only around 20–30...
consolidation deficits have been demonstrated. Like ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, though, this is attributable to Doppel gene expression. However, spatial learning, a predominantly hippocampal-function, is decreased in the null mice and can be recovered with the reinstatement of PrP in neurons; this indicates that loss of PrP function is the cause. The interaction of hippocampal PrP with laminin
Laminin
Laminins are major proteins in the basal lamina , a protein network foundation for most cells and organs...
(LN) is pivotal in memory processing and is likely modulated by the kinases PKA and ERK1/2.
Further support for PrP’s role in memory formation is derived from several population studies. A test of healthy young humans showed increased long-term memory ability associated with an MM or MV genotype when compared to VV. Down Syndrome
Down syndrome
Down syndrome, or Down's syndrome, trisomy 21, is a chromosomal condition caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British physician who described the syndrome in 1866. The condition was clinically described earlier in the 19th...
patients with a single valine
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
substitution have been linked to earlier cognitive decline. Several polymorphisms in PRNP have been linked with cognitive impairment in the elderly as well as earlier cognitive decline. All of these studies investigated differences in codon 129, indicating its importance in the overall functionality of PrP, particularly in regard to memory.
Neurons and synapses
PrP is present in both pre- and post-synaptic neuron cell, and the great concentration is in the pre-synaptic cells. Considering this and PrP’s suite of behavioral influences, the neural cell functions and interactions are of particular interest. Based on the copper ligand, one proposed function casts PrP as a copper buffer for the synaptic cleft. In this role, the protein could serve as either a copper homeostasisHomeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
mechanism, a calcium modulator, or a sensory for copper or oxidative stress. Loss of PrP function has been linked to long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
(LTP). This effect can be positive or negative and is due to changes in neuronal excitability and synaptic transmission in the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
.
Some research indicates PrP involvement in neuronal development, differentiation, and neurite
Neurite
A neurite refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture, because it can be difficult to tell axons from dendrites before...
outgrowth. The PrP-activated signal transduction pathway is associated with axon and dendritic outgrowth with a series of kinases.
Immune system
Though most attention is focused on PrP’s presence in the nervous system, it is also abundant in immune system tissue. PrP immune cells include haematopoietic stem cells, mature lymphoid and myeloid compartments, and certain lymphocytes; also, it has been detected in natural killer cells, platelets, and monocytes. T cellT cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
activation is accompanied by a strong up-regulation of PrP, though it is not requisite. The lack of immuno-response to transmissible spongiform encephalopathy
Transmissible spongiform encephalopathy
Transmissible spongiform encephalopathies , also known as prion diseases, are a group of progressive conditions that affect the brain and nervous system of many animals, including humans. According to the most widespread hypothesis they are transmitted by prions, though some other data suggest an...
(TSE), neurdegenerative diseases caused by prions, could stem from the tolerance for PrPSC.
Muscles, liver, and pituitary
PrP-null mice provide clues to a role in muscular physiology when subjected to a forced swimming test, which showed reduced locomotor activity. Aging mice with an overexpression of PRNP showed significant degration of muscle tissue.Though present, very low levels of PrP exist in the liver and could to be associated with liver fibrosis. Presence in the pituitary has been shown to affect neuroendrocrine function in amphibians, but little is known concerning mammalian pituitary PrP.
Cell life cycle
Varying expression of PrP through the cell's life cycle has led to speculation on involvement in development. A wide range of studies has been conducted investigating the role in cell proliferation, differentiation, death, and survival.Cell signaling
Engagement of PrP has been linked to activation of signal transduction in several cases. Modulation of signal transduction pathways has been demonstrated in cross-linking with antibodies and ligand-binding (hop/STI1 or copper).Cellular scaffolding
Given the diversity of interactions, effects, and distribution, PrP has been proposed as dynamic surface protein functioning in signaling pathways. Specific sites along the protein bind other proteins, biomolecules, and metals. These interfaces allow specific sets of cells to communicate based on level of expression and the surrounding microenvironment. The anchoring on a GPI raft in the lipid bilayer supports claims of an extracellular scaffolding function.Diseases caused by PrP misfolding
More than 20 mutations in the PRNP gene have been identified in people with inherited prion diseases, which include the following:- Creutzfeldt-Jakob diseaseCreutzfeldt-Jakob diseaseCreutzfeldt–Jakob disease or CJD is a degenerative neurological disorder that is incurable and invariably fatal. CJD is at times called a human form of mad cow disease, given that bovine spongiform encephalopathy is believed to be the cause of variant Creutzfeldt–Jakob disease in humans.CJD...
- glutamic acidGlutamic acidGlutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...
-200 is replaced by lysineLysineLysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
while valineValineValine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
is present at amino acid 129 - Gerstmann-Sträussler-Scheinker syndromeGerstmann-Sträussler-Scheinker syndromeGerstmann–Sträussler–Scheinker syndrome is a very rare, usually familial, fatal neurodegenerative disease that affects patients from 20 to 60 years in age...
- usually a change in codon 102 from prolineProlineProline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
to leucineLeucineLeucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins... - fatal familial insomniaFatal familial insomniaFatal familial insomnia is a very rare autosomal dominant inherited prion disease of the brain. It is almost always caused by a mutation to the protein PrPC, but can also develop spontaneously in patients with a non-inherited mutation variant called sporadic fatal insomnia...
- aspartic acidAspartic acidAspartic acid is an α-amino acid with the chemical formula HOOCCHCH2COOH. The carboxylate anion, salt, or ester of aspartic acid is known as aspartate. The L-isomer of aspartate is one of the 20 proteinogenic amino acids, i.e., the building blocks of proteins...
-178 is replaced by asparagineAsparagineAsparagine is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side-chain's functional group. It is not an essential amino acid...
while methionineMethionineMethionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
is present at amino acid 129
Some PRNP mutations lead to a change in single amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s (the building blocks of proteins) in the prion protein. Others insert additional amino acids into the protein or cause an abnormally short protein to be made. These mutations cause the cell to make prion proteins with an abnormal structure. The abnormal protein, PrPSc, accumulates in the brain and destroys nerve cells, which leads to the mental and behavioral features of prion diseases.
Several other changes in the PRNP gene (called polymorphisms) do not cause prion diseases, but may affect a person's risk of developing these diseases or alter the course of the disorders. An allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
which codes for a PRNP variant — G127V provides resistance to Kuru
Kuru (disease)
Kuru is an incurable degenerative neurological disorder that is a type of transmissible spongiform encephalopathy, caused by a prion found in humans...
.
The conversion of PrPC to PrPSC conformation is the mechanism of transmission of fatal, neurodegenerative transmissible spongiform encephalopathies (TSE). This can arise from genetic factors, infection from external source, or spontaneously for reasons unknown. Accumulation of PrPSC corresponds with progression of neurodegeneration and is the proposed cause.
A variety of mutations in the PRNP gene have resulted in inherited prion diseases.
- Creutzfeldt-Jakob diseaseCreutzfeldt-Jakob diseaseCreutzfeldt–Jakob disease or CJD is a degenerative neurological disorder that is incurable and invariably fatal. CJD is at times called a human form of mad cow disease, given that bovine spongiform encephalopathy is believed to be the cause of variant Creutzfeldt–Jakob disease in humans.CJD...
- glutamic acidGlutamic acidGlutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...
-200 is replaced by lysineLysineLysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
while valineValineValine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
is present at amino acid 129 - Gerstmann-Sträussler-Scheinker syndromeGerstmann-Sträussler-Scheinker syndromeGerstmann–Sträussler–Scheinker syndrome is a very rare, usually familial, fatal neurodegenerative disease that affects patients from 20 to 60 years in age...
- usually a change in codon 102 from prolineProlineProline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
to leucineLeucineLeucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins... - fatal familial insomniaFatal familial insomniaFatal familial insomnia is a very rare autosomal dominant inherited prion disease of the brain. It is almost always caused by a mutation to the protein PrPC, but can also develop spontaneously in patients with a non-inherited mutation variant called sporadic fatal insomnia...
- aspartic acidAspartic acidAspartic acid is an α-amino acid with the chemical formula HOOCCHCH2COOH. The carboxylate anion, salt, or ester of aspartic acid is known as aspartate. The L-isomer of aspartate is one of the 20 proteinogenic amino acids, i.e., the building blocks of proteins...
-178 is replaced by asparagineAsparagineAsparagine is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side-chain's functional group. It is not an essential amino acid...
while methionineMethionineMethionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
is present at amino acid 129
Additionally, some prion diseases can be transmitted from external sources of PrPSC.
- ScrapieScrapieScrapie is a fatal, degenerative disease that affects the nervous systems of sheep and goats. It is one of several transmissible spongiform encephalopathies , which are related to bovine spongiform encephalopathy and chronic wasting disease of deer. Like other spongiform encephalopathies, scrapie...
- fatal neurodegenerative disease in sheep, not transmissible to humans - Bovine spongiform encephalopathyBovine spongiform encephalopathyBovine spongiform encephalopathy , commonly known as mad-cow disease, is a fatal neurodegenerative disease in cattle that causes a spongy degeneration in the brain and spinal cord. BSE has a long incubation period, about 30 months to 8 years, usually affecting adult cattle at a peak age onset of...
(mad-cow disease) - fatal neurodegenerative disease in cows, which can be transmitted to humans by ingestion of brain, spinal, or digestive tract tissue of an infected cow - Kuru - TSE in humans, transmitted via cannibalism
Interactions
PRNP has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Hop
Hop (protein)
Hop, occasionally written HOP, is an abbreviation for Hsp70-Hsp90 Organizing Protein. It functions as a co-chaperone which reversibly links together the protein chaperones Hsp70 and Hsp90....
.
A strong interaction exists between PrP and cochaperone Hsp70
Hsp70
The 70 kilodalton heat shock proteins are a family of ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms...
/Hsp90
Hsp90
Hsp90 is a molecular chaperone and is one of the most abundant proteins expressed in cells. It is a member of the heat shock protein family, which is upregulated in response to stress...
organizing protein/Stress-induced protein 1 (hop (protein)
Hop (protein)
Hop, occasionally written HOP, is an abbreviation for Hsp70-Hsp90 Organizing Protein. It functions as a co-chaperone which reversibly links together the protein chaperones Hsp70 and Hsp90....
/STI1).