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The cellular prion protein mediates neurotoxic signalling of ?-sheet-rich conformers independent of prion replication.

ABSTRACT: Formation of aberrant protein conformers is a common pathological denominator of different neurodegenerative disorders, such as Alzheimer's disease or prion diseases. Moreover, increasing evidence indicates that soluble oligomers are associated with early pathological alterations and that oligomeric assemblies of different disease-associated proteins may share common structural features. Previous studies revealed that toxic effects of the scrapie prion protein (PrP(Sc)), a ?-sheet-rich isoform of the cellular PrP (PrP(C)), are dependent on neuronal expression of PrP(C). In this study, we demonstrate that PrP(C) has a more general effect in mediating neurotoxic signalling by sensitizing cells to toxic effects of various ?-sheet-rich (?) conformers of completely different origins, formed by (i) heterologous PrP, (ii) amyloid ?-peptide, (iii) yeast prion proteins or (iv) designed ?-peptides. Toxic signalling via PrP(C) requires the intrinsically disordered N-terminal domain (N-PrP) and the GPI anchor of PrP. We found that the N-terminal domain is important for mediating the interaction of PrP(C) with ?-conformers. Interestingly, a secreted version of N-PrP associated with ?-conformers and antagonized their toxic signalling via PrP(C). Moreover, PrP(C)-mediated toxic signalling could be blocked by an NMDA receptor antagonist or an oligomer-specific antibody. Our study indicates that PrP(C) can mediate toxic signalling of various ?-sheet-rich conformers independent of infectious prion propagation, suggesting a pathophysiological role of the prion protein beyond of prion diseases.

SUBMITTER: Resenberger UK

PROVIDER: S-EPMC3098494 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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The cellular prion protein mediates neurotoxic signalling of β-sheet-rich conformers independent of prion replication.

Resenberger Ulrike K UK Harmeier Anja A Woerner Andreas C AC Goodman Jessica L JL Müller Veronika V Krishnan Rajaraman R Vabulas R Martin RM Kretzschmar Hans A HA Lindquist Susan S Hartl F Ulrich FU Multhaup Gerd G Winklhofer Konstanze F KF Tatzelt Jörg J

The EMBO journal 20110325 10

Formation of aberrant protein conformers is a common pathological denominator of different neurodegenerative disorders, such as Alzheimer's disease or prion diseases. Moreover, increasing evidence indicates that soluble oligomers are associated with early pathological alterations and that oligomeric assemblies of different disease-associated proteins may share common structural features. Previous studies revealed that toxic effects of the scrapie prion protein (PrP(Sc)), a β-sheet-rich isoform o ...[more]

PMID: 21441896

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Project description:The formation of ?-sheet rich prion oligomers and fibrils from native prion protein (PrP) is thought to be a key step in the development of prion diseases. Many methods are available to convert recombinant prion protein into ?-sheet rich fibrils using various chemical denaturants (urea, SDS, GdnHCl), high temperature, phospholipids, or mildly acidic conditions (pH 4). Many of these methods also require shaking or another form of agitation to complete the conversion process. We have identified that shaking alone causes the conversion of recombinant PrP to ?-sheet rich oligomers and fibrils at near physiological pH (pH 5.5 to pH 6.2) and temperature. This conversion does not require any denaturant, detergent, or any other chemical cofactor. Interestingly, this conversion does not occur when the water-air interface is eliminated in the shaken sample. We have analyzed shaking-induced conversion using circular dichroism, resolution enhanced native acidic gel electrophoresis (RENAGE), electron microscopy, Fourier transform infrared spectroscopy, thioflavin T fluorescence and proteinase K resistance. Our results show that shaking causes the formation of ?-sheet rich oligomers with a population distribution ranging from octamers to dodecamers and that further shaking causes a transition to ?-sheet fibrils. In addition, we show that shaking-induced conversion occurs for a wide range of full-length and truncated constructs of mouse, hamster and cervid prion proteins. We propose that this method of conversion provides a robust, reproducible and easily accessible model for scrapie-like amyloid formation, allowing the generation of milligram quantities of physiologically stable ?-sheet rich oligomers and fibrils. These results may also have interesting implications regarding our understanding of prion conversion and propagation both within the brain and via techniques such as protein misfolding cyclic amplification (PMCA) and quaking induced conversion (QuIC).

Dataset Information

The cellular prion protein mediates neurotoxic signalling of ?-sheet-rich conformers independent of prion replication.

Publications

The cellular prion protein mediates neurotoxic signalling of β-sheet-rich conformers independent of prion replication.

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