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Major prion protein (PrP), is encoded in the human by the ''PRNP''
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 b ...
also known as CD230 (
cluster of differentiation The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophen ...
230). Expression of the
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
is most predominant in the
nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes ...
but occurs in many other tissues throughout the body. The protein can exist in multiple
isoforms 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 iso ...
: the normal PrPC form, and the
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 ...
-resistant form designated PrPRes such as the disease-causing PrPSc(scrapie) and an isoform located in
mitochondria A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...
. The
misfolded 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 reproduc ...
version PrPSc is associated with a variety of cognitive disorders and neurodegenerative diseases such as in animals: ovine scrapie,
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, mad cow disease), feline spongiform encephalopathy, transmissible mink encephalopathy (TME), exotic ungulate encephalopathy, chronic wasting disease (CWD) which affects
cervids Deer or true deer are hoofed ruminant mammals forming the family Cervidae. The two main groups of deer are the Cervinae, including the muntjac, the elk (wapiti), the red deer, and the fallow deer; and the Capreolinae, including the rei ...
; and in humans:
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), fatal familial insomnia (FFI),
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),
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, ...
, and variant Creutzfeldt–Jakob disease (vCJD). Similarities exist between kuru, thought to be due to human ingestion of diseased individuals, and vCJD, thought to be due to human ingestion of BSE-tainted cattle products.


Gene

The human ''PRNP'' gene is located on the short (p) arm of chromosome 20 between the end (terminus) of the arm and position 13, from
base pair A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both D ...
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-strand antiparallel
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 ...
, an NH2-terminal tail, and a short COOH-terminal tail. A glycophosphatidylinositol (GPI) membrane anchor at the COOH-terminal tethers PrP to
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
s, and this proves to be integral to the transmission of conformational change; secreted PrP lacking the anchor component is unaffected by the infectious isoform. The primary sequence of PrP is 253
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 ...
s long before
post-translational modification Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribo ...
. Signal sequences in the
amino In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent ...
- and carboxy- terminal ends are removed posttranslationally, resulting in a mature length of 208 amino acids. For human and golden hamster PrP, two
glycosylated Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
sites exist on helices 2 and 3 at Asn181 and Asn197.
Murine The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. Members of this subfamily are called murines. In terms of species richness, this subfamily is larger than all mammal families ex ...
PrP has glycosylation sites as Asn180 and Asn196. A
disulfide 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 ...
bond exists between Cys179 of the second helix and Cys214 of the third helix (human PrPC numbering). PrP
messenger RNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the p ...
contains a
pseudoknot __NOTOC__ 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 ...
structure ( prion pseudoknot), which is thought to be involved in regulation of PrP
protein translation In molecular biology and genetics, translation is the process in which ribosomes in the cytoplasm or endoplasmic reticulum synthesize proteins after the process of transcription of DNA to RNA in the cell's nucleus. The entire process is ...
.


Ligand-binding

The mechanism for conformational conversion to the scrapie isoform is speculated to be an elusive
ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
-protein, but, so far, no such compound has been identified. However, a large body of research has developed on candidates and their interaction with the PrPC.
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 ...
,
zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...
,
manganese Manganese is a chemical element with the symbol Mn and atomic number 25. It is a hard, brittle, silvery metal, often found in minerals in combination with iron. Manganese is a transition metal with a multifaceted array of industrial alloy use ...
, and
nickel Nickel is a chemical element with symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel is a hard and ductile transition metal. Pure nickel is chemically reactive but large pieces are slow to ...
are confirmed PrP ligands that bind to its octarepeat region. Ligand binding causes a conformational change with unknown effect. Heavy metal binding at PrP has been linked to resistance to
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
arising from
heavy metal toxicity A toxic heavy metal is any relatively dense metal or metalloid that is noted for its potential toxicity, especially in environmental contexts. The term has particular application to cadmium, Mercury (element), mercury and lead, all of which app ...
.


PrPC (normal cellular) isoform

Although the precise function of PrP is not yet known, it is possibly involved in the transport of
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 ...
ic copper to cells from the surrounding environment. Researchers have also proposed roles for PrP in cell signaling or in the formation 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. PrPC attaches to the outer surface of the
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
by a
glycosylphosphatidylinositol 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 in ...
anchor at its
C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
Ser Ser or SER may refer to: Places * Ser, a village in Bogdand Commune, Satu Mare County, Romania * Serpens (Ser), an astronomical constellation of the northern hemisphere * Serres, known as Ser in Serbian, a city in Macedonia, Greece Organization ...
231.
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 ...
contains five octapeptide repeats with sequence PHGGGWGQ (though the first repeat has the slightly-modified,
histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the de ...
-deficient sequence PQGGGGWGQ). This is thought to generate a copper-
binding domain In molecular biology, binding domain is a protein domain which binds to a specific atom or molecule, such as calcium or DNA. A protein domain is a part of a protein sequence and a tertiary structure that can change or evolve, function, and live ...
via nitrogen atoms in the histidine
imidazole Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole Diazole refers ...
side-chains and deprotonated
amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...
nitrogens from the 2nd and 3rd glycines in the repeat. The ability to bind copper is, therefore, pH-dependent.
NMR Nuclear magnetic resonance (NMR) is a physical phenomenon in which nuclei in a strong constant magnetic field are perturbed by a weak oscillating magnetic field (in the near field) and respond by producing an electromagnetic signal with ...
shows copper binding results in a conformational change at the
N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
.


PrPSc (scrapie) isoform

PrPSc is a conformational isoform of PrPC, but this orientation tends to accumulate in compact,
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 ...
-resistant aggregates within neural tissue. The abnormal PrPSc isoform has a different
secondary Secondary may refer to: Science and nature * Secondary emission, of particles ** Secondary electrons, electrons generated as ionization products * The secondary winding, or the electrical or electronic circuit connected to the secondary winding i ...
and
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 int ...
from PrPC, but identical primary sequence. Circular dichroism shows that normal PrPC has 42%
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 ear ...
and 3%
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 ...
content, whereas PrPSc is only 30% alpha helix and 43% beta sheet. However, the presence of alpha helices in infectious PrPSc has come into question, with current models proposing a lack of alpha helices altogether, replaced instead with a total beta sheet composition. This refolding renders the PrPSc isoform extremely resistant to
proteolysis Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...
. The propagation of PrPSc is a topic of great interest, as its accumulation is a pathological cause of
neurodegeneration 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 ...
. Based on the progressive nature 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 Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating cells ...
. Polymorphisms at sites 136, 154, and 171 are associated with varying susceptibility to ovine scrapie. (These ovine sites correspond to human sites 133, 151, and 168.) Polymorphisms of the PrP-VRQ form and PrP-ARQ form are associated with increased susceptibility, whereas PrP-ARR is associated with resistance. The National Scrapie Plan of the UK 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.


Function


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 A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...
mice to investigate deficiencies and differences. Initial attempts produced two strains of PrP-null mice that show no physiological or developmental differences when subjected 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 Purkinje cells, or Purkinje neurons, are a class of GABAergic inhibitory neurons located in the cerebellum. They are named after their discoverer, Czech anatomist Jan Evangelista Purkyně, who characterized the cells in 1839. Structure The ...
in the
cerebellum The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebel ...
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 A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., Endogeny (biology), endogeno ...
is altered in null mice.
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 ...
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 memory Short-term memory (or "primary" or "active memory") is the capacity for holding a small amount of information in an active, readily available state for a short interval. For example, short-term memory holds a phone number that has just been recit ...
,
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 ...
consolidation deficits have been demonstrated. As with
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 ...
, however, this is attributable to Doppel gene expression. However,
spatial learning In cognitive psychology and neuroscience, spatial memory is a form of memory responsible for the recording and recovery of information needed to plan a course to a location and to recall the location of an object or the occurrence of an event. Sp ...
, 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 Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major components of the basal lamina (one of the layers of the basement membrane), the protein network foundation for most cells and organs. The laminins ...
(LN) is pivotal in memory processing and is likely modulated by the
kinases In biochemistry, a kinase () is an enzyme that catalysis, catalyzes the transfer of phosphate groups from High-energy phosphate, high-energy, phosphate-donating molecules to specific Substrate (biochemistry), substrates. This process is known as ...
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 or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual dis ...
patients with a single
valine Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotonat ...
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, in particular with regard to memory.


Neurons and synapses

PrP is present in both the pre- and post-synaptic compartments, with the greatest concentration in the pre-synaptic portion. 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 Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...
. In this role, the protein could serve as either a copper
homeostasis In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
mechanism, a calcium modulator, or a sensor for copper or oxidative stress. Loss of PrP function has been linked to
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 ...
(LTP). This effect can be positive or negative and is due to changes in neuronal excitability and synaptic transmission in the
hippocampus 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, a ...
. Some research indicates PrP involvement in neuronal development, differentiation, and
neurite A neurite or neuronal process 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 ...
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 hematopoietic stem cells, mature lymphoid and myeloid compartments, and certain
lymphocytes A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adap ...
; also, it has been detected in
natural killer cells Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...
,
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 ...
, and
monocytes Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also infl ...
.
T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
activation is accompanied by a strong up-regulation of PrP, though it is not requisite. The lack of immunoresponse to
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 ...
(TSE), neurodegenerative 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 degradation of muscle tissue. Though present, very low levels of PrP exist in the liver and could be associated with liver fibrosis. Presence in the pituitary has been shown to affect neuroendocrine function in amphibians, but little is known concerning mammalian pituitary PrP.


Cellular

Varying expression of PrP through the
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
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. Engagement of PrP has been linked to activation of
signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
. Modulation of signal transduction pathways has been demonstrated in cross-linking with antibodies and ligand-binding (hop/STI1 or copper). 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 The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...
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 disease Prions are misfolded proteins that have the ability to transmit their misfolded shape onto normal variants of the same protein. They characterize several fatal and transmissible neurodegenerative diseases in humans and many other animals. It i ...
s, which include the following: *
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 ...
glutamic acid Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...
-200 is replaced by
lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
while
valine Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotonat ...
is present at amino acid 129 *
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 ...
– usually a change in
codon The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accomplished by the ribosome, which links ...
102 from
proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...
to
leucine Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- ca ...
* fatal familial insomnia
aspartic acid Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
-178 is replaced by
asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
while
methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ro ...
is present at amino acid 129 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. Some ''PRNP'' mutations lead to a change in single
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 ...
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 An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chro ...
that codes for a PRNP variant, G127V, provides resistance to
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, ...
. * In addition, some prion diseases can be transmitted from external sources of PrPSc. *
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 ...
– fatal neurodegenerative disease in sheep, not transmissible to humans *
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 ...
(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 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, ...
– TSE in humans, transmitted via funerary cannibalism. Generally, affected family members were given, by tradition, parts of the central nervous system according to ritual when consuming deceased family members.


Alzheimer's disease

PrPC protein is one of several cellular receptors of soluble
amyloid beta Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which is ...
(Aβ) oligomers, which are canonically implicated in causing
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 ...
. These
oligomer In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relativ ...
s are composed smaller Aβ plaques, and are the most damaging to the integrity of a
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
. The precise mechanism of soluble Aβ oligomers directly inducing
neurotoxicity Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specificall ...
is unknown, and experimental deletion of ''PRNP'' in animals has yielded several conflicting findings. When Aβ oligomers were injected into the cerebral ventricles of a mouse model of Alzheimer's, ''PRNP'' deletion did not offer protection, only anti-PrPC antibodies prevented long-term memory and
spatial learning In cognitive psychology and neuroscience, spatial memory is a form of memory responsible for the recording and recovery of information needed to plan a course to a location and to recall the location of an object or the occurrence of an event. Sp ...
deficits. This would suggest either an unequal relation between PRNP and Aβ oligomer-mediated
neurodegeneration 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 ...
or a site-specific relational significance. In the case of direct injection of Aβ oligomers into the
hippocampus 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, a ...
, ''PRNP''-knockout mice were found to be indistinguishable from control with respect to both neuronal death rates and measurements of
synaptic plasticity In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuit ...
. It was further found that Aβ-oligomers bind to PrPC at the
postsynaptic density The postsynaptic density (PSD) is a protein dense ''specialization'' attached to the postsynaptic membrane. PSDs were originally identified by electron microscopy as an electron-dense region at the membrane of a postsynaptic neuron. The PSD is in ...
, indirectly overactivating the
NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA rece ...
via the
Fyn Funen ( da, Fyn, ), with an area of , is the third-largest island of Denmark, after Zealand and Vendsyssel-Thy. It is the 165th-largest island in the world. It is located in the central part of the country and has a population of 469,947 as ...
enzyme, resulting in
excitotoxicity In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate re ...
. Soluble Aβ oligomers also bind to PrPC at the
dendritic spines A dendritic spine (or spine) is a small membranous protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical si ...
, forming a complex with Fyn and excessively activating
tau Tau (uppercase Τ, lowercase τ, or \boldsymbol\tau; el, ταυ ) is the 19th letter of the Greek alphabet, representing the voiceless dental or alveolar plosive . In the system of Greek numerals, it has a value of 300. The name in English ...
, another protein implicated in Alzheimer's. As the gene
FYN Funen ( da, Fyn, ), with an area of , is the third-largest island of Denmark, after Zealand and Vendsyssel-Thy. It is the 165th-largest island in the world. It is located in the central part of the country and has a population of 469,947 as ...
codes for the enzyme Fyn, FYN-knockout mice display neither
excitotoxic In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate re ...
events nor dendritic spine shrinkage when injected with Aβ oligomers. In mammals, the full functional significance of PRNP remains unclear, as ''PRNP'' deletion has been prophylactically implemented by the cattle industry without apparent harm. In mice, this same deletion
phenotypically In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
varies between Alzheimer's mouse lines, as hAPPJ20 mice and TgCRND8 mice show a slight increase in
epileptic Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...
activity, contributing to conflicting results when examining Alzheimer's survival rates. Of note, the deletion of ''PRNP'' in both APPswe and SEN1dE9, two other
transgenic A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...
models of Alzheimer's, attenuated the epilepsy-induced death phenotype seen in a subset of these animals. Taken collectively, recent evidence suggests PRNP may be important for conducing the neurotoxic effects of soluble Aβ-oligomers and the emergent disease state of Alzheimer's. In humans, the
methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ro ...
/
valine Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotonat ...
polymorphism at
codon The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accomplished by the ribosome, which links ...
129 of ''PRNP'' (rs1799990) is most closely associated with Alzheimer's disease. Variant V
allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chro ...
carriers (VV and MV) show a 13% decreased risk with respect to developing Alzheimer's compared to the methionine
homozygote Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...
(MM). However, the protective effects of variant V carriers have been found exclusively in Caucasians. The decreased risk in V allele carriers is further limited to late-onset Alzheimer's disease only (≥ 65 years). PRNP can also functionally interact with polymorphisms in two other genes implicated in Alzheimer's,
PSEN1 Presenilin-1 (PS-1) is a presenilin protein that in humans is encoded by the ''PSEN1'' gene. Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid beta ( ...
and
APOE Apolipoprotein E (APOE) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular disease. APOE belongs to a family of fat-binding proteins called apolipoproteins. ...
, to compound risk for both Alzheimer's and sporadic Creutzfeldt–Jakob disease. A
point mutation A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...
on codon 102 of ''PRNP'' at least in part contributed to three separate patients' atypical
frontotemporal dementia Frontotemporal dementia (FTD), or frontotemporal degeneration disease, or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of frontal and temporal lobes. FTDs broadly present as ...
within the same family, suggesting a new phenotype for
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 ...
. The same study proposed sequencing ''PRNP'' in cases of ambiguously diagnosed dementia, as the various forms of
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 ...
can prove challenging to differentially diagnose.


Interactions

A strong
interaction Interaction is action that occurs between two or more objects, with broad use in philosophy and the sciences. It may refer to: Science * Interaction hypothesis, a theory of second language acquisition * Interaction (statistics) * Interactions o ...
exists between PrP and the
cochaperone Co-chaperones are proteins that assist chaperones in protein folding and other functions. Co-chaperones are the non-client binding molecules that assist in protein folding mediated by Hsp70 and Hsp90. They are particularly essential in stimulation ...
Hop A hop is a type of jump. Hop or hops may also refer to: Arts and entertainment * ''Hop'' (film), a 2011 film * Hop! Channel, an Israeli TV channel * ''House of Payne'', or ''HOP'', an American sitcom * Lindy Hop, a swing dance of the 1920s and ...
(
Hsp70 The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an importa ...
/
Hsp90 Hsp90 (heat shock protein 90) is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, ...
organizing protein; also called STI1 (Stress-induced protein 1)).


References


External links

* PRNP (PrP) gene a
GeneCard
*
Susan Lindquist's Seminar: "The Surprising World of Prion Biology"
{{DEFAULTSORT:Prnp Clusters of differentiation Amyloidosis