The N-Terminal, Polybasic Region of PrPC Dictates the Efficiency of Prion Propagation by Binding to PrPSc

Abstract

Prion propagation involves a templating reaction in which the infectious form of the prion protein (PrP Sc) binds to the cellular form (PrP C), generating additional molecules of PrP Sc. While several regions of the PrP C molecule have been suggested to play a role in PrP Sc formation based on in vitro studies, the contribution of these regions in vivo is unclear. Here, we report that mice expressing PrP deleted for a short, polybasic region at the N terminus (residues 23–31) display a dramatically reduced susceptibility to prion infection and accumulate greatly reduced levels of PrP Sc. These results, in combination with biochemical data, demonstrate that residues 23–31 represent a critical site on PrP C that binds to PrP Sc and is essential for efficient prion propagation. It may be possible to specifically target this region for treatment of prion diseases as well as other neurodegenerative disorders due to β-sheet-rich oligomers that bind to PrP C.

A C-terminal Membrane Anchor Affects the Interactions of Prion Proteins with Lipid Membranes

“…Liposomes via Their C-terminal Membrane Anchors-To assess the binding of prion proteins to liposomes, a flotation assay in a discontinuous iodixanol gradient (36,31, and 5% (v/v) iodixanol) was used (26,33). Two kinds of phospholipid liposomes, DPPC (a temperature-dependent gel-phase, noncharged phospholipid) and POPG (an anionic phospholipid), were mixed with PrP constructs and loaded underneath the iodixanol gradient.…”

“…Indeed, Wang et al (33) already determined that this region initiates (electrostatic) interaction between PrP and anionic phospholipids. Moreover, Turnbaugh et al (36) recently found that this polybasic region dictates the efficiency of prion propagation by binding to PrP Sc . A deletion of this region can dramatically reduce susceptibility of prion protein to prion infection and significantly elongate the survival of transgenic (⌬23-31 PrP) mice after scrapie inoculation (36).…”

Homodimerization as a molecular switch between low and high efficiency PrPCcell surface delivery and neuroprotective activity

“…In prion diseases, the N-terminal polybasic residues of PrP C bind PrP Sc and are required for efficient prion propagation. 41 Increasing extracellular PrPN1 levels would be expected to prevent PrP Sc binding to the neuronal surface and inhibit prion conversion and induction of intracellular toxic signals. However, several issues should be addressed prior to envisaging a therapeutic avenue based on PrPN1.…”

Cyclin-dependent Kinase 5 Phosphorylation of Familial Prion Protein Mutants Exacerbates Conversion into Amyloid Structure

“…The N terminus of PrP is also clearly involved in familial and transmissible prion diseases. Additional octapeptide repeats are observed in familial human PrP diseases (33), and mice lacking the N-terminal amino acids 32-93 and 23-31 are less susceptible to transmissible prion diseases (34,35). Furthermore, the N terminus of PrP has been associated with numerous cellular features such as lipid rafts (36), RNA binding (37), micropinocytosis (38), and neuroprotection (39,40).…”