Orchestrating Neurotrophic Activities 63 Prion Protein : Orchestrating Neurotrophic Activities

PrPC is highly expressed in both the central and peripheral nervous systems from early stages of development and in adulthood. Its major conformational change and conversion into an abnormal form (PrPSc) has been associated with the generation of prions, the infectious agent of transmissible spongiform encephalopathies (TSEs). The massive neurodegeneration presented by individuals suffering from these diseases has been associated with the gain of neurotoxic activity of PrPSc. On the other hand, major neurodegeneration is also observed in transgenic mice expressing PrPC molecules deleted of specific domains, which points to important functional domains within this molecule, and supports the hypothesis that loss-of PrPC function may contribute to the pathogenesis of TSEs. Furthermore, a large body of data demonstrates direct or indirect interaction of PrPC with extracellular matrix proteins, soluble factors, transmembrane proteins, G-protein coupled receptors and ions channels. The ability of PrPC to drive the assembly of multi-component complexes at the cell surface is likely the basis for its neurotrophic functions. These properties indicate that PrPC may be relevant for not only the spongiform encephalophaties, but also as an ancillary component of the pathogenesis of other neurodegenerative diseases, and therefore amenable to therapeutic targeting. The prion protein and the neurotrophic theory The neurotrophic theory originally referred to the idea that all body organs were dependent on nutritional factors secreted by the nervous system (Levine, 1992). However, and more akin with Cajal ́s theories on the neurotrophic activity of the Schwann cell (Azmitia, 2002), the theory gained momentum upon the discovery of the properties of the nerve growth factor NGF (Levi-Montalcini, 1987). Then, its central tenet became that the survival of neurons during development of the nervous system was determined by the limited availability of trophic molecules delivered by target organs to the nerve terminals (Oppenheim, 1989). In parallel with the discoveries concerning a wide range of effects of NGF (Levi-Montalcini et al., 1996), work in the 1980s and 1990s greatly expanded the scope of the neurotrophic theory. Adding to the original emphasis on the role of individual target-derived neurotrophins (Thoenen et al., 1993), current neurotrophic theory allows for the operation of multiple neurotrophic systems upon single neurons (Davies, 1996), the production and physiological release of neurotrophic factors by glia (Sariola and Saarma, 2003), the role of afferent-derived molecules (Linden, 1994), trophic effects of both neurotransmitters and neuromodulators (Linden et al., 2005; Martins and Pearson, 2008), as well as cytokines (Krieglstein and Unsicker, 1996; Middleton et al., 2000) and hormones (Datson et al., 2008; Williams, 2008), and encompasses not only the survival but also the differentiation and functional integrity of components of the nervous system, among other complexities (Chao and Bothwell, 2002; Chao, 2003; Kalb, 2005; Levi-Montalcini and Calissano, 2006). Neurotrophic interactions are based on cell-cell communication through either the release or the presentation at the cell surface, of specific molecules that bind to other molecules present in a target cell. The latter may be either the same cell, providing for autocrine effects, a neighboring cell or even reside at a distance, depending on both the neurotrophic factor and the structure and diffusion properties of the tissue environment. Both cell surface (Huang and Reichardt, 2003; Blochl and Blochl, 2007) and intracellular (Datson et al., 2008), including nuclear (Williams, 2008) receptors, serve as docking elements for the neurotrophic agents, and activate multiple signaling pathways leading to neurotrophic effects. Cell surface receptors constitute the majority of the targets of neurotrophic agents, and they can transfer signals through the plasma membrane either through their own intracellular domains, or via the activation of transmembrane partners (Yano and Chao, 2000; Runeberg-Roos and Saarma, 2007). Evidence that the prion protein (PrPC) is involved in neurotrophic activity first appeared from studies in which the expression of PrPC prevented cell death triggered by serum deprivation of a hippocampal cell line (Kuwahara et al., 1999). It was subsequently shown that engagement of PrPC with antibodies triggered cell signaling (Mouillet-Richard et al., 2000), and that interaction of PrPC with a soluble binding partner induced neurotrophic-like effects mediated by the cAMP-protein kinase A and Mitogen activated protein kinase (MAPK) pathways (Chiarini et al., 2002; Zanata et al., 2002; Lopes et al., 2005). Evidence that PrPC mediates neurotrophic interactions is now both abundant and compelling (e.g. (Nishimura et al., 2004; McLennan et al., 2004; Spudich et al., 2005; Coulpier et al., 2006; Rangel et al., 2007; Nazor et al., 2007; Weise et al., 2008; Rambold et al., 2008). The hypothesis has been put forward that the prion protein functions as a dynamic cell surface platform for the assembly of signaling modules, based on which selective interactions with many ligands and transmembrane signaling pathways translate into wide-range consequences Horizon Scientific Press. http://www.horizonpress. com Curr. Issues Mol. Biol. 12: 63-86. Online journal at http://www.cimb. org