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 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 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<unk>  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, long-term memory consolidation deficits have been demonstrated. As with ataxia, however, 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<unk>  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 (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. 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; 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 immunoresponse to transmissible spongiform encephalopathies (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<unk>  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 neuroendrocrine function in amphibians, but little is known concerning mammalian pituitary PrP. Cellular Varying expression of PrP through the cell 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. Engagement of PrP has been linked to activation of signal transduction. 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 supports claims of an extracellular scaffolding function.
PRNP
SCoRS
QNS
DDAIP
TOFI
CLaCS
OHVIRA
MALOVA