Abstract
The physiological functions of PrPC 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 PrPC 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.
Highlights
PrPC is an endogenous GPI-anchored protein that is highly expressed in some neuronal and glial populations of the telencephalon (e.g., [1,2,3])
Despite the large number of studies reporting the neurotoxicity of different prion peptides, we indicate that the synthetic peptide comprising the central domain (CD) domain is highly neurotoxic due to its inability to transform protofibrillar structures to mature fibrils
In order to decrease variability between peptide samples, three batches (#1, #2 and #3) of each peptide were purchased from Invitrogen or Sigma Aldrich or synthesized by UQC
Summary
PrPC is an endogenous GPI-anchored protein that is highly expressed in some neuronal and glial populations of the telencephalon (e.g., [1,2,3]). From a mechanistic point of view, some studies have reported that membrane modifications or the putative endocytosis of PrP106–126 mediate its neurotoxic effects [24,25] in contrast to others [26], it has been reported that the peptide is able to modify membrane viscosity properties [27]. This is important if we take into account that membrane binding of PrPC is required to induce neurotoxicity [28] (see [6,29] for a review)
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