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 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 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