User:Kevonze/sandbox

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Major prion protein (PrP) is a human protein encoded by PRNP gene on chromosome 20.[1] Expression is infamously most predominant in the nervous system but occurs in many tissues throughout the body.[2] Human PrP is associated with a variety of cognitive deficiencies and neurodegenerative diseases such as Creutzfeld-Jakob disease, bovine spongiform encephalopathy, and kuru (disease).

Structure[edit]

PrP structure is highly conserved through mammals, lending credence to application of conclusions from test animals such as mice.[3] Comparison between primates is especially similar, ranging from 92.9-99.6% similarity in amino acid sequences. The human protein structure is comprised 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.[4] 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.[5]

Conformations[edit]

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-resistant aggregates within neural tissue.[6] 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.[7] Strong support for this is taken from studies in which PRNP-knockout mice are resistant to the introduction of PrPSC.[8] Despite widespread acceptance of the conformation conversion hypothesis, some studies mitigate claims for a direct link between PrPSC and cytotoxicity.[9]

Ligand-Binding[edit]

The mechanism for conformational conversion is speculated to be an elusive ligand-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.[10] 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+.[11] The binding caused a conformational change, with unknown effect. The copper-PrP interaction has been linked to resistance to oxidative stress.[12]

Functions[edit]

Nervous System[edit]

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.[13] 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.[10]

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.[14] Other observed differences include reduced stress response and increased exploration of novel environments.[15][16]

Circadian rhythm is altered in null mice.[2] 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.[17] In addition, circadian regulation has been demonstrated in PrP mRNA, which cycles regularly with day-night.[18]

Memory[edit]

While null mice exhibit normal learning ability and short-term memory, 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.[19][20] The interaction of hippocampal PrP with laminin (LN) is pivotal in memory processing and is likely modulated by the kinases PKA and ERK1/2.[21][22]

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.[23] Down Syndrome patients with a single valine substitution have been linked to earlier cognitive decline.[24] Several polymorphisms in PRNP have been linked with cognitive impairment in the elderly as well as earlier cognitive decline.[25][26][27] 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[edit]

PrP is present in both pre- and post-synaptic neuron cell, and the great concentration is in the pre-synaptic cells.[28] 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 sensory for copper or oxidative stress.[29] 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.[30][31]

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.[9][32]

Immune System[edit]

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 cell 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.[33]

Muscles, Liver, and Pituitary[edit]

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.[10]

Cell Life Cycle[edit]

Varying expression of PrP through the cell's life cycle has lead to speculation on involvement in development. A wide range of studies have been conducted investigating the role in cell proliferation, differentiation, death, and survival.[10]

Cell Signaling[edit]

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).[10]

Cellular Scaffolding[edit]

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.[10]

Interactions[edit]

A strong interaction exists between PrP and cochaperone Hsp70/Hsp90 organizing protein/Stress-induced protein 1 (hop (protein)/STI1).[34]

Transmissible Spongiform Encephalopathies[edit]

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.[37]

  • Scrapie - fatal neurodegenerative disease in sheep, not transmissible to humans
  • Bovine spongiform encephalopathy (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

References[edit]

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