Neurotoxicity of prion peptides mimicking the central domain of the cellular prion protein

PLoS One. 2013 Aug 5;8(8):e70881. doi: 10.1371/journal.pone.0070881. Print 2013.

Abstract

The physiological functions of PrP(C) remain enigmatic, but the central domain, comprising highly conserved regions of the protein may play an important role. Indeed, a large number of studies indicate that synthetic peptides containing residues 106-126 (CR) located in the central domain (CD, 95-133) of PrP(C) are neurotoxic. The central domain comprises two chemically distinct subdomains, the charge cluster (CC, 95-110) and a hydrophobic region (HR, 112-133). The aim of the present study was to establish the individual cytotoxicity of CC, HR and CD. Our results show that only the CD peptide is neurotoxic. Biochemical, Transmission Electron Microscopy and Atomic Force Microscopy experiments demonstrated that the CD peptide is able to activate caspase-3 and disrupt the cell membrane, leading to cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Benzothiazoles
  • Caspase 3 / metabolism
  • Cell Membrane Permeability / drug effects
  • Cells, Cultured
  • Dimyristoylphosphatidylcholine / chemistry
  • Enzyme Activation
  • Fluorescent Dyes / chemistry
  • Kinetics
  • Lipid Bilayers / chemistry
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Mimicry
  • Molecular Sequence Data
  • Neurons / drug effects
  • Neurons / physiology*
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology
  • Peptide Fragments / physiology*
  • PrPC Proteins / chemistry
  • PrPC Proteins / pharmacology
  • PrPC Proteins / physiology*
  • Primary Cell Culture
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Thiazoles / chemistry

Substances

  • Benzothiazoles
  • Fluorescent Dyes
  • Lipid Bilayers
  • Peptide Fragments
  • PrPC Proteins
  • Thiazoles
  • thioflavin T
  • Casp3 protein, mouse
  • Caspase 3
  • Dimyristoylphosphatidylcholine

Grants and funding

This research was supported by funding from FP7-PRIORITY and DEMTEST (Joint Programming of Neurodegenerative Diseases), MINECO (BFU2012-32617), Generalitat de Catalunya (SGR2009-366), the Instituto Salud Carlos III to JADR and Fondo de Investigaciones Sanitarias (PI11-00075) to RG and MINECO (CTQ2008-00177) to MR. CV and ON are supported by the Spanish Ministry of Science and Innovation (MICINN) and Fundación Ramón Areces respectively. SV is a Juan de la Cierva post-doctoral fellow of the MICINN. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.