Prion diseases are neurodegenerative disorders characterized by a hallmark event involving the posttranslational misfolding of the normal cellular prion protein (PrPC) into an infectious and toxic protease-resistant conformation (PrPSc). Studies on identification of the pathological prion species and on the mechanisms involved in triggering neuronal death have been hampered by the heterogeneous nature of PrPSc aggregates. The use of synthetic PrP-derived peptides has made possible exploration of the relationship between amino acid sequence, biophysical structure and biological effect. Indeed, most PrP-derived peptides replicate the fundamental aspects of full-length PrPSc, including: a β- sheet-rich structure; destabilization of lipid membranes; intracellular calcium dysregulation; increased oxidative stress; activation of pro-apoptotic signaling pathways; and, more contentiously, neurotoxicity dependent upon endogenous PrPC expression. Crucially, in vivo toxicity of the important PrP-peptides, e.g. PrP(106-126) and PrP(118-135), has additionally been established. Therefore, the use of prion-derived peptides facilitates the development of therapeutic strategies based on small-molecule inhibitors of aggregation and other pharmacological agents that protect against the lethal effect of these peptides in vivo.
Keywords: Prion protein, synthetic peptide, ion channel-forming peptides, membrane physiology, calcium homeostasis, apoptosis, neurotoxicity, oxidative stress, intracellular signaling, amyloidoses
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