Major prion protein

The major prion protein is encoded in the human body by the PRNP gene also known as CD230. Expression of the protein is most prominent in the nervous system but occurs in many other tissues throughout the body.
The protein can exist in multiple isoforms: the normal PrP^C form, and the protease-resistant form designated PrP^Res such as the disease-causing PrP^Sc and an isoform located in mitochondria. The misfolded version PrP^Sc is associated with a variety of uniformly fatal neurodegenerative diseases in humans and nonhuman species. In nonhuman species these include ovine scrapie, bovine spongiform encephalopathy, feline spongiform encephalopathy, transmissible mink encephalopathy, exotic ungulate encephalopathy, chronic wasting disease which affects deer; human prion diseases include Creutzfeldt–Jakob disease, fatal familial insomnia, Gerstmann–Sträussler–Scheinker syndrome, kuru, and variant Creutzfeldt–Jakob disease. 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 arm of chromosome 20 between the end of the arm and position 13, from base pair 4,615,068 to base pair 4,630,233.

Structure

PrP is highly conserved in mammals, lending credence to conclusions derived from experimental animals such as mice. In primates, PrP ranges from 92.9% to 99.6% similarity in amino acid sequences.
The 3-dimensional structure of human PrP consists of a globular domain with three α-helices and a two-strand antiparallel β-sheet, an NH₂-terminal tail, and a short COOH-terminal tail. A glycophosphatidylinositol membrane anchor at the COOH-terminal tethers PrP to cell membranes, 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 acids long before post-translational modification. Signal sequences in the amino- and carboxy- terminal ends are removed posttranslationally, resulting in a mature length of 208 amino acids. For human and golden hamster PrP, two glycosylated sites exist on helices 2 and 3 at Asn181 and Asn197. Murine PrP has glycosylation sites as Asn180 and Asn196. A disulfide bond exists between Cys179 of the second helix and Cys214 of the third helix.
PrP messenger RNA contains a pseudoknot structure, which is thought to be involved in regulation of PrP protein translation.

Ligand-binding

The conformational conversion of PrP to the scrapie isoform has been speculated to be linked to an elusive ligand-protein, but, so far, no such agent has been identified. However, a large body of research has developed on candidates and their interaction with the PrP^C.
Copper, zinc, manganese, and nickel 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 arising from heavy metal toxicity.

PrP^C (normal cellular) isoform

The precise function of PrP is not yet known. It may play a role in the transport of ionic copper into cells from the surrounding environment. Researchers have also proposed roles for PrP in cell signaling or in the formation of synapses. PrP^C attaches to the outer surface of the cell membrane by a glycosylphosphatidylinositol anchor at its C-terminal Ser231.
PrP contains five octapeptide repeats with sequence PHGGGWGQ. This is thought to generate a copper-binding domain via nitrogen atoms in the histidine imidazole side-chains and deprotonated amide nitrogens from the 2nd and 3rd glycines in the repeat. The ability to bind copper is, therefore, pH-dependent. NMR shows copper binding results in a conformational change at the N-terminus.

PrP^Sc (scrapie) isoform

PrP^Sc is a conformational isoform of PrP^C that tends to accumulate in compact, protease-resistant aggregates within neural tissue. The abnormal PrP^Sc isoform has a different secondary and tertiary structure from PrP^C, but identical primary sequence. Whereas PrP^C has largely alpha helical and disordered domains, PrP^Sc has no alpha helix and an amyloid fibril core composed of a stack of PrP molecules bound together by parallel in-register intermolecular beta sheets. This refolding renders the PrP^Sc isoform extremely resistant to proteolysis.
The propagation of PrP^Sc is a topic of great interest, as its accumulation is linked to neurodegeneration. Based on the progressive nature of spongiform encephalopathies, the predominant hypothesis posits that normal PrP^C is compelled to misfold and aggregate due to its interaction with PrP^Sc. Strong support for this is taken from studies in which PRNP-knockout mice are resistant to the introduction of PrP^Sc. Despite widespread acceptance of the conformation conversion hypothesis, some studies mitigate claims for a direct link between PrP^Sc and cytotoxicity.
Polymorphisms at sites 136, 154, and 171 are associated with varying susceptibility to ovine scrapie. 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 of PrP with neurodegenerative diseases raises questions as to the normal function of PrP in the brain. A common approach to this problem is to use PrP-knockout and transgenic 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 PrP-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.

Memory

While PrP-deficient mice exhibit normal learning ability and short-term memory, long-term memory consolidation deficits have been demonstrated. As with ataxia, this is attributable to Doppel gene expression. However, spatial learning, a function predominantly mediated by the hippocampus, 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 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. In Down syndrome a single valine substitution has been associated with 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. In this role, the protein could serve as either a copper homeostasis mechanism, a calcium modulator, or a sensor for copper or oxidative stress. Loss of PrP function has been linked to long-term potentiation. This effect can be positive or negative and is due to changes in neuronal excitability and synaptic transmission in the hippocampus.
Some research indicates that PrP is involved in neuronal development, differentiation, and neurite outgrowth. The PrP-activated signal transduction pathway is associated with axon and dendritic outgrowth.

Immune system

Though most attention is focused on the presence of PrP in the nervous system, it is also abundant in cells of the immune system, including hematopoietic stem cells, mature lymphoid and myeloid compartments, and certain lymphocytes. PrP also has been detected in natural killer cells, platelets, and monocytes. T cell activation is accompanied by a strong up-regulation of PrP, though it is not requisite. The lack of a strong immune response to transmissible spongiform encephalopathies, neurodegenerative diseases caused by prions, could stem from the tolerance for native PrP^Sc.

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.
Very low levels of PrP exist in the liver and could be associated with liver fibrosis. The presence of PrP in the pituitary has been shown to affect neuroendocrine function in amphibians, but little is known concerning PrP in the mammalian pituitary.