Proteasomal dysfunction and endoplasmic reticulum stress enhance trafficking of prion protein aggregates through the secretory pathway and increase accumulation of pathologic prion protein.

A conformational change of the cellular prion protein (PrP(c)) underlies formation of PrP(Sc), which is closely associated with pathogenesis and transmission of prion diseases. The precise conformational prerequisites and the cellular environment necessary for this post-translational process remain to be completely elucidated. At steady state, glycosylated PrP(c) is found primarily at the cell surface, whereas a minor fraction of the population is disposed of by the ER-associated degradation-proteasome pathway.

Conditional modulation of membrane protein expression in cultured cells mediated by prion protein recognition of short phosphorothioate oligodeoxynucleotides.

We demonstrate that the levels of native as well as transfected prion protein (PrP) are lowered in various cell lines exposed to phosphorothioate oligodeoxynucleotides (PS-DNA) and can be rapidly reverted to their normal amounts by removal of PS-DNA. This transient modulation was independent of the glycosylation state of PrP, and in addition, all three PrP glycoforms were susceptible to PS-DNA treatment. Deletion of the N-terminal domain (amino acids 23-99), but not of the other domains of PrP, abrogated its PS-DNA-mediated down-regulation.

Prion protein interaction with stress-inducible protein 1 enhances neuronal protein synthesis via mTOR.

Transmissible spongiform encephalopathies are fatal neurodegenerative diseases caused by the conversion of prion protein (PrP(C)) into an infectious isoform (PrP(Sc)). How this event leads to pathology is not fully understood. Here we demonstrate that protein synthesis in neurons is enhanced via PrP(C) interaction with stress-inducible protein 1 (STI1).

The novel sorting nexin SNX33 interferes with cellular PrP formation by modulation of PrP shedding.

The cellular prion protein (PrP(c)) is a glycosyl-phosphatidylinositol (GPI)-anchored protein trafficking in the secretory and endocytic pathway and localized mainly at the plasma membrane. Conversion of PrP(c) into its pathogenic isoform PrP(Sc) is associated with pathogenesis and transmission of prion diseases. Intramolecular cleavage in the middle, the extreme C-terminal part or within the GPI anchor and shedding of PrP(c) modulate this conversion process by reducing the substrate for prion formation.

Strategies for eliminating PrP(c) as substrate for prion conversion and for enhancing PrP(Sc) degradation.

Prion diseases are fatal neurodegenerative infectious disorders for which no therapeutic or prophylactic regimens exist. Our work aims to eliminate PrP(c) as substrate for the conversion into PrP(Sc) and to increase the cellular clearance capacity of PrP(Sc). In order to achieve the first objective, we used chemical compounds which interfere with the subcellular trafficking of PrP(c), e.

Charged bipolar suramin derivatives induce aggregation of the prion protein at the cell surface and inhibit PrPSc replication.

The conversion of the cellular prion protein (PrPc) into a pathogenic isoform (PrP(Sc)) is one of the underlying events in the pathogenesis of the fatal transmissible spongiform encephalopathies (TSEs). Numerous compounds have been described to inhibit prion replication and PrP(Sc) accumulation in cell culture. Among these, the drug suramin induces aggregation and re-targeting of PrPc to endocytic compartments.

Recognition of lumenal prion protein aggregates by post-ER quality control mechanisms is mediated by the preoctarepeat region of PrP.

Prion diseases are fatal transmissible neurodegenerative disorders linked to an aberrant conformation of the cellular prion protein (PrP(c)). We have shown previously that the chemical compound suramin induced aggregation of fully matured PrP(c) in post-ER compartments, thereby, activating a post-ER quality control mechanism and preventing cell surface localization of PrP by intracellular re-routing of aggregated PrP from the Golgi/TGN directly to lysosomes. Of note, drug-induced PrP aggregates were not toxic and could easily be degraded by neuronal cells.

Prion diseases: from molecular biology to intervention strategies.

Prion diseases are fatal neurodegenerative infectious disorders for which no therapeutic or prophylactic regimens exist. Understanding the molecular process of conformational conversion of the cellular prion protein (PrP(c)) into its pathological isoform (PrP(Sc)) will be necessary to devise effective antiprion strategies. In recent years, new findings in the cell biology of PrP(c), in the molecular pathogenesis of PrP(Sc), and in the cellular quality control mechanisms involved in these scenarios have accumulated.

Essential role of the prion protein N terminus in subcellular trafficking and half-life of cellular prion protein.

Aberrant metabolism and conformational alterations of the cellular prion protein (PrP(c)) are the underlying causes of transmissible spongiform encephalopathies in humans and animals. In cells, PrP(c) is modified post-translationally and transported along the secretory pathway to the plasma membrane, where it is attached to the cell surface by a glycosylphosphatidylinositol anchor. In surface biotinylation assays we observed that deletions within the unstructured N terminus of murine PrP(c) led to a significant reduction of internalization of PrP after transfection of murine neuroblastoma cells.