Prion diseases are
neurodegenerative disorders of the central nervous system of humans and animals, characterized by spongiform degeneration of the central nervous system,
astrogliosis, and deposition of
amyloid into the brain. The conversion of a cellular
glycoprotein (
prion protein, PrP(C)) into an altered
isoform (PrP(Sc)) has been proposed to represent the causative event responsible for these diseases. The
peptide corresponding to the residues 106-126 of PrP sequence (PrP106-126) is largely used to explore the neurotoxic mechanisms underlying the
prion diseases. We investigated the intracellular signaling responsible for PrP106-126-dependent cell death in the SH-SY5Y human
neuroblastoma cell line. In these cells, PrP106-126 treatment induced apoptotic cell death and the activation of
caspase-3. The
p38 MAP-kinase blockers (
SB203580 and
PD169316) prevented the apoptotic cell death evoked by PrP106-126 and Western blot analysis revealed that the exposure of the cells to the
peptide induced p38 activation. However, whether the neuronal toxicity of PrP106-126 is caused by a soluble or fibrillar form of this
peptide is still unknown. In this study, we correlated the structural state of this
peptide with its neurotoxicity. We show that the two conserved glycines in position 114 and 119 prevent the
peptide to assume a structured conformation, favoring its aggregation in
amyloid fibrils. The substitution of both glycines with
alanine residues (PrP106-126AA) generates a soluble nonamyloidogenic
peptide, that retained its toxic properties when incubated with
neuroblastoma cells. These data show that the
amyloid aggregation is not necessary for the induction of the toxic effects of PrP106-126.