The cellular prion protein traps Alzheimer's Aβ in an oligomeric form and disassembles amyloid fibers.
1847 - 1858
MetadataShow full item record
There is now strong evidence to show that the presence of the cellular prion protein (PrP(C)) mediates amyloid-β (Aβ) neurotoxicity in Alzheimer's disease (AD). Here, we probe the molecular details of the interaction between PrP(C) and Aβ and discover that substoichiometric amounts of PrP(C), as little as 1/20, relative to Aβ will strongly inhibit amyloid fibril formation. This effect is specific to the unstructured N-terminal domain of PrP(C). Electron microscopy indicates PrP(C) is able to trap Aβ in an oligomeric form. Unlike fibers, this oligomeric Aβ contains antiparallel β sheet and binds to a oligomer specific conformational antibody. Our NMR studies show that a specific region of PrP(C), notably residues 95-113, binds to Aβ oligomers, but only once Aβ misfolds. The ability of PrP(C) to trap and concentrate Aβ in an oligomeric form and disassemble mature fibers suggests a mechanism by which PrP(C) might confer Aβ toxicity in AD, as oligomers are thought to be the toxic form of Aβ. Identification of a specific recognition site on PrP(C) that traps Aβ in an oligomeric form is potentially a therapeutic target for the treatment of Alzheimer's disease.
AuthorsYounan, ND; Sarell, CJ; Davies, P; Brown, DR; Viles, JH
Showing items related by title, author, creator and subject.
Rowling, PJ; Sivertsson, EM; Perez-Riba, A; Main, ER; Itzhaki, LS (2015-10)Studying protein folding and protein design in globular proteins presents significant challenges because of the two related features, topological complexity and co-operativity. In contrast, tandem-repeat proteins have ...
Arbeloa, A; Garnett, J; Lillington, J; Bulgin, RR; Berger, CN; Lea, SM; Matthews, S; Frankel, G (2009-12)We investigated how the type III secretion system WxxxE effectors EspM2 of enterohaemorrhagic Escherichia coli, which triggers stress fibre formation, and SifA of Salmonella enterica serovar Typhimurium, which is involved ...
Gold, VAM; Whitehouse, S; Robson, A; Collinson, I (2013-02-01)The motor ATPase SecA drives protein secretion through the bacterial Sec complex. The PPXD (pre-protein cross-linking domain) of the enzyme has been observed in different positions, effectively opening and closing a clamp ...