Properties and Pathogenicity of Prion-Derived Peptides (original) (raw)
Prion diseases are neurodegenerative disorders characterized by a hallmark event involving the post-translational misfolding of the normal cellular prion protein (PrP C) into an infectious and toxic protease-resistant confor-mation (PrP Sc). 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 PrP Sc 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 PrP Sc , including: a-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 PrP C 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.
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The cellular prion protein (PrP(C)), a cell surface glycoprotein involved in prion disorders, has been shown to mediate the toxicity of several pathological aggregates, including its own misfolded state and some oligomeric assemblies of the amyloid β peptide, which are thought to be primarily responsible for the synaptic dysfunction characterizing Alzheimer's disease. Thus, elucidating the physiological function of PrP(C), and how it could be corrupted by the interaction with misfolded proteins, may provide important insights to understand the pathological processes of prion and Alzheimer's diseases, and possibly other neurodegenerative disorders. In this manuscript, we review the data supporting a role for PrP(C) at the intersection of different neurodegenerative diseases, discuss potential mechanisms by which this protein could mediate neurotoxic signals, and examine therapeutic approaches that may arise from the identification of PrP(C)-directed compounds.
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