Homodimerization as a molecular switch between low and high efficiency PrP C cell surface delivery and neuroprotective activity

Prion. Mar-Apr 2013;7(2):170-4. doi: 10.4161/pri.23583. Epub 2013 Jan 28.

Abstract

PrP (C) is associated with a variety of functions, and its ability to interact with a multitude of partners, including itself, may largely explain PrP multifunctionality and the lack of consensus on the genuine physiological function of the protein in vivo. In contrast, there is a consensus in the literature that alterations in PrP (C) trafficking and intracellular retention result in neuronal degeneration. In addition, a proteolytic modification in the late secretory pathway termed the α-cleavage induces the secretion of PrPN1, a PrP (C) -derived metabolite with fascinating neuroprotective activity against toxic oligomeric Aβ molecules implicated in Alzheimer disease. Thus, studies focusing on understanding the regulation of PrP (C) trafficking to the cell surface and the modulation of α-cleavage are essential. The objective of this commentary is to highlight recent evidences that PrP (C) homodimerization stimulates trafficking of the protein to the cell surface and results in high levels of PrPN1 secretion. We also discuss a hypothetical model for these results and comment on future challenges and opportunities.

Keywords: Alzheimer disease; dimerization; neuroprotection; prion; protein secretion; β-sheet oligomers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cattle
  • Cell Membrane / metabolism
  • Cricetinae
  • Humans
  • Mice
  • Models, Biological
  • Neuroprotective Agents / chemistry*
  • Neuroprotective Agents / metabolism*
  • PrPC Proteins / chemistry*
  • PrPC Proteins / metabolism*
  • Protein Multimerization

Substances

  • Neuroprotective Agents
  • PrPC Proteins