Physiology of the Prion Protein

Abstract

Prion diseases are transmissible spongiform encephalopathies (TSEs), attributed to conformational conversion of the cellular prion protein (PrP(C)) into an abnormal conformer that accumulates in the brain. Understanding the pathogenesis of TSEs requires the identification of functional properties of PrP(C). Here we examine the physiological functions of PrP(C) at the systemic, cellular, and molecular level. Current data show that both the expression and the engagement of PrP(C) with a variety of ligands modulate the following: 1) functions of the nervous and immune systems, including memory and inflammatory reactions; 2) cell proliferation, differentiation, and sensitivity to programmed cell death both in the nervous and immune systems, as well as in various cell lines; 3) the activity of numerous signal transduction pathways, including cAMP/protein kinase A, mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt pathways, as well as soluble non-receptor tyrosine kinases; and 4) trafficking of PrP(C) both laterally among distinct plasma membrane domains, and along endocytic pathways, on top of continuous, rapid recycling. A unified view of these functional properties indicates that the prion protein is 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 upon both physiology and behavior.

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

“…Among the myriad of interactions described, Hsp60 (Edenhofer et al, 1996), STI1 (Zanata et al, 2002), Bcl-2 (Kurschner and Morgan, 1995), and Grb2 (Spielhaupter and Schatzl, 2001) have been proposed as PrP c ligands. However, only a small proportion of these related pathways are functional in a physiological context (see (Lee et al, 2003) or (Westergard et al, 2007) and (Linden et al, 2008) for reviews). Two in vitro studies demonstrate that PrP c binds to the laminin receptor 67K (Gauczynski et al, 2001) and the adhesion molecule N-CAM (Santuccione et al, 2005;Schmitt-Ulms et al, 2001), both transducing survival signals or promoting neurite outgrowth.…”

“…Readers interested in immunological or other aspects of PrP c biology (e.g., transmission, detection, analyses of human diseases, etc.) are referred to recent reviews (e.g., (Aguzzi et al, 2008a;Aguzzi et al, 2007;Aguzzi et al, 2008b;Linden et al, 2008)). …”

“…In mammals, PrP c is expressed in several tissues, such as secondary lymphoid organs, heart, and neural tissue (see (Ford et al, 2002;Linden et al, 2008;Miele et al, 2003) for examples), with lower levels found in kidney and liver (Miele et al, 2003;Tichopad et al, 2003). In the brain, maximal Prnp mRNA expression is observed in the adult neocortex and cerebellum.…”

“…In this regard, PrP c is considered a dynamic cell-surface platform for the assembly of signaling molecules which may participate in neuronal processes, including neuronal differentiation (see (Linden et al, 2008) for additional review).…”

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

“…Determining the function of PrP C has proved to be a major challenge, complicated by the fact that PrP knock-out mice lack an obvious phenotype [12]. Many different putative functions have been proposed, indicating that PrP C is a multifunctional protein that plays a role in cell signaling [13,14] and metal metabolism [15][16][17]. When PrP aggregates and forms fibrils, however, it has significantly changed conformation and becomes largely insoluble and proteinase K resistant.…”