期刊
EMBO JOURNAL
卷 30, 期 10, 页码 2057-2070出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/emboj.2011.86
关键词
Alzheimer; intrinsically disordered; NMDA receptor; oligomer; prion
资金
- Deutsche Forschungsgemeinschaft [SFB 596, GRK 1123]
- Max Planck Society
- BMBF [DIP5.1]
- HHMI
- NIH [GM25874, NS067782]
- German Center for Neurodegenerative Diseases (DZNE)
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 (PrPSc), a beta-sheet-rich isoform of the cellular PrP (PrPC), are dependent on neuronal expression of PrPC. In this study, we demonstrate that PrPC has a more general effect in mediating neurotoxic signalling by sensitizing cells to toxic effects of various beta-sheet-rich (beta) conformers of completely different origins, formed by (i) heterologous PrP, (ii) amyloid beta-peptide, (iii) yeast prion proteins or (iv) designed beta-peptides. Toxic signalling via PrPC 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 PrPC with beta-conformers. Interestingly, a secreted version of N-PrP associated with beta-conformers and antagonized their toxic signalling via PrPC. Moreover, PrPC-mediated toxic signalling could be blocked by an NMDA receptor antagonist or an oligomer-specific antibody. Our study indicates that PrPC can mediate toxic signalling of various beta-sheet-rich conformers independent of infectious prion propagation, suggesting a pathophysiological role of the prion protein beyond of prion diseases. The EMBO Journal (2011) 30, 2057-2070. doi: 10.1038/emboj.2011.86; Published online 25 March 2011
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