Novel aspects of prions, their receptor molecules, and innovative approaches for TSE therapy

Abstract

1. Prion diseases are a group of rare, fatal neurodegenerative diseases, also known as transmissible spongiform encephalopathies (TSEs), that affect both animals and humans and include bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep, chronic wasting disease (CWD) in deer and elk, and Creutzfeldt-Jakob disease (CJD) in humans. TSEs are usually rapidly progressive and clinical symptoms comprise dementia and loss of movement coordination due to the accumulation of an abnormal isoform (PrP(Sc)) of the host-encoded prion protein (PrP(c)). 2. This article reviews the current knowledge on PrP(c) and PrP(Sc), prion replication mechanisms, interaction partners of prions, and their cell surface receptors. Several strategies, summarized in this article, have been investigated for an effective antiprion treatment including development of a vaccination therapy and screening for potent chemical compounds. Currently, no effective treatment for prion diseases is available. 3. The identification of the 37 kDa/67 kDa laminin receptor (LRP/LR) and heparan sulfate as cell surface receptors for prions, however, opens new avenues for the development of alternative TSE therapies.

Fig. 1.

Schematic view of structural elements of the murine cellular prion protein. The depicted murine cellular PrP (PrP^c) is a GPI-anchored protein of 254 amino acid residues. During PrP^c processing, a 22 amino acid N-terminal signal peptide (SP) is removed and 23 carboxy-terminal amino acid residues (signal sequence (SS)) are cleaved upon the addition of the glycosylphosphatidyl inositol anchor to Ser-231. The N-terminal region contains a series of four octapeptide repeats that have been implicated in the binding of metal ions (Whittal et al., 2000). The first repeat represents a nonarepeat due to an additional glycin residue. The repeat has a histidine residue substituted by a glutamine and, therefore, fails to bind copper (Leliveld et al., 2006). The globular C-terminus of the molecule folds into three α-helices and an antiparallel ß-sheet, whereas the N-terminal part of the protein is flexible as determined in solution. The structure of the murine PrP 121-231 was initially solved by Riek and colleagues (Riek et al., 1996), and that of hamster PrP 29-231 by Donne and colleagues (Donne et al., 1997).

Fig. 2.

Cellular functions of LRP/LR and model of the LRP/LR-/HSPG-dependent PrP^c and PrP^Sc binding and internalization. Upper panel: LRP/LR is associated to ribosomes and is involved in the translation machinery (i), binds to nuclear DNA through its association with histones contributing to the maintenance of nuclear structures (ii), and acts as a receptor for laminin, elastin, and carbohydrates, as well as viruses and PrP^c and PrP^Sc. Lower panel: PrP^c (green circle) anchored by glycosylphosphatidyl inositol (GPI) (green bar) becomes internalized by LRP/LR (yellow ovals) (Gauczynski et al., 2001) utilizing HSPGs (light green bars and black chain) as cofactors/coreceptors (Hundt et al., 2001). PrP^Sc (purple squares) binds to the cell surface in a LRP/LR-(Gauczynski et al., 2006), and heparan sulfate (black chain)/ HSPG- (Horonchik et al., 2005) dependent manner. The PrP/LRP-LR/HSPG complex becomes internalized into endo-/lysosomes. LRP/LR (Morel et al., ; Gauczynski et al., 2006) and heparan sulfates (Horonchik et al., 2005) mediate presumably in synergy PrP^Sc internalization. Polysulfated glycans such as the heparan mimetics HM 2602 and HM 5004 (red chain) block PrP^Sc binding to the cells by competing with the binding to heparan sulfate and LRP/LR (Gauczynski et al., 2006). Pentosan polysulfate (SP-54) and phycarin sulfate may have similar effects as the HMs (adopted from (Gauczynski et al., 2006)). AAV denotes Adeno-Associated Virus.