Prion proteins in signal transduction (original) (raw)
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Transmissible and genetic prion diseases share a common pathway of neurodegeneration
Nature, 1999
Prion diseases can be infectious, sporadic and genetic. The infectious forms of these diseases, including bovine spongiform encephalopathy and Creutzfeldt-Jakob disease, are usually characterized by the accumulation in the brain of the transmissible pathogen, an abnormally folded isoform of the prion protein (PrP) termed PrPSc. However, certain inherited PrP mutations appear to cause neurodegeneration in the absence of PrPSc, working instead by favoured synthesis of CtmPrP, a transmembrane form of PrP. The relationship between the neurodegeneration seen in transmissible prion diseases involving PrPSc and that associated with ctmPrP has remained unclear. Here we find that the effectiveness of accumulated PrPSc in causing neurodegenerative disease depends upon the predilection of host-encoded PrP to be made in the ctmPrP form. Furthermore, the time course of PrPSc accumulation in transmissible prion disease is followed closely by increased generation of CtmPrP. Thus, the accumulation ...
The biology of the cellular prion protein
Neurochemistry International, 2002
Prions are the etiological agents for infectious degenerative encephalopaties acting by inducing conformational changes in the cellular prion protein (PrPc), which is a cell membrane GPI anchored glycoprotein. Besides its conservation among species and expression in most tissues, and in particular, in high levels in the nervous system, the role for cellular prion protein remained obscure for some time. Initial skepticism about such a role was mainly due to the absence of a gross phenotype alteration in cellular prion protein null mice. In the last few years, some possible biological functions for cellular prion protein have been described. Copper binds to the molecule and the resulting complex may be responsible for cell protection against oxidative stress. Cellular prion protein is also a high-affinity ligand for laminin, and induces neuronal cell adhesion, neurite extension and maintenance. The binding site resides in a carboxy-terminal peptide of the γ-1 chain, which is very conserved among all laminin types, indicating that this interaction may be relevant in other tissues besides the brain. Moreover, cellular prion protein association with a peptide that mimics a putative ligand at the cell surface, p66, triggers neuroprotective signals through a cAMP/PKA-dependent pathway. Since PrPc recycles from membrane to an intracellular compartment, which is induced by copper binding, it is also possible that the internalization mechanism allows switching off elicited signals.
Virus research, 2014
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.