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A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers.

Cohen SI, Arosio P, Presto J, Kurudenkandy FR, Biverstål H, Dolfe L, Dunning C, Yang X, Frohm B, Vendruscolo M, Johansson J, Dobson CM, Fisahn A, Knowles TP, Linse S - Nat. Struct. Mol. Biol. (2015)

Bottom Line: Recent studies have revealed that once Aβ42 fibrils are generated, their surfaces effectively catalyze the formation of neurotoxic oligomers.We demonstrate in vitro that Brichos achieves this inhibition by binding to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves minimal formation of toxic oligomeric intermediates.These results reveal that molecular chaperones can help maintain protein homeostasis by selectively suppressing critical microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Cambridge, Cambridge, UK.

ABSTRACT
Alzheimer's disease is an increasingly prevalent neurodegenerative disorder whose pathogenesis has been associated with aggregation of the amyloid-β peptide (Aβ42). Recent studies have revealed that once Aβ42 fibrils are generated, their surfaces effectively catalyze the formation of neurotoxic oligomers. Here we show that a molecular chaperone, a human Brichos domain, can specifically inhibit this catalytic cycle and limit human Aβ42 toxicity. We demonstrate in vitro that Brichos achieves this inhibition by binding to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves minimal formation of toxic oligomeric intermediates. We verify that this mechanism occurs in living mouse brain tissue by cytotoxicity and electrophysiology experiments. These results reveal that molecular chaperones can help maintain protein homeostasis by selectively suppressing critical microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation.

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Related in: MedlinePlus

Brichos inhibits the catalytic cycle that generates toxic Aβ42 oligomersSchematic diagram showing (a) the molecular pathways – primary and secondary nucleation – involved in oligomer formation in Aβ42 aggregation and (b) the mechanism by which Brichos suppresses the formation of toxic oligomers, in which the secondary nucleation pathway is specifically inhibited to suppress the remove source of oligomers.
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Figure 6: Brichos inhibits the catalytic cycle that generates toxic Aβ42 oligomersSchematic diagram showing (a) the molecular pathways – primary and secondary nucleation – involved in oligomer formation in Aβ42 aggregation and (b) the mechanism by which Brichos suppresses the formation of toxic oligomers, in which the secondary nucleation pathway is specifically inhibited to suppress the remove source of oligomers.

Mentions: The results that have emerged from this study show that the chaperone Brichos targets a highly specific molecular process in the aggregation pathway of Aβ42, that of fibril-induced secondary nucleation, which is predominantly responsible for the generation of toxic oligomers. Indeed, by inhibiting secondary nucleation, the reaction network underlying the Aβ42 aggregation process (Fig. 6a) is fundamentally altered such that the modified pathway leading from monomeric peptide to fibrils proceeds through primary nucleation and elongation-related processes alone (Fig. 6b), and results in significantly lower concentrations of toxic oligomers (Fig. 4b). The reduction in the population of these species originates from the fact that out of the two processes generating oligomers, primary and secondary nucleation, the chaperone has specifically removed the source that is dominant in Aβ42 aggregation19, namely secondary nucleation (Fig. 6b). It is this ability to turn off the otherwise continuing and increasing generation of oligomers through secondary nucleation that explains the efficacy of this process. It is interesting to note, however, that this reduction in oligomer population occurs even though the eventual quantities of mature fibrils, which are now generated through primary nucleation and elongation alone, remain unaffected by the presence of Brichos19,20.


A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers.

Cohen SI, Arosio P, Presto J, Kurudenkandy FR, Biverstål H, Dolfe L, Dunning C, Yang X, Frohm B, Vendruscolo M, Johansson J, Dobson CM, Fisahn A, Knowles TP, Linse S - Nat. Struct. Mol. Biol. (2015)

Brichos inhibits the catalytic cycle that generates toxic Aβ42 oligomersSchematic diagram showing (a) the molecular pathways – primary and secondary nucleation – involved in oligomer formation in Aβ42 aggregation and (b) the mechanism by which Brichos suppresses the formation of toxic oligomers, in which the secondary nucleation pathway is specifically inhibited to suppress the remove source of oligomers.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4595974&req=5

Figure 6: Brichos inhibits the catalytic cycle that generates toxic Aβ42 oligomersSchematic diagram showing (a) the molecular pathways – primary and secondary nucleation – involved in oligomer formation in Aβ42 aggregation and (b) the mechanism by which Brichos suppresses the formation of toxic oligomers, in which the secondary nucleation pathway is specifically inhibited to suppress the remove source of oligomers.
Mentions: The results that have emerged from this study show that the chaperone Brichos targets a highly specific molecular process in the aggregation pathway of Aβ42, that of fibril-induced secondary nucleation, which is predominantly responsible for the generation of toxic oligomers. Indeed, by inhibiting secondary nucleation, the reaction network underlying the Aβ42 aggregation process (Fig. 6a) is fundamentally altered such that the modified pathway leading from monomeric peptide to fibrils proceeds through primary nucleation and elongation-related processes alone (Fig. 6b), and results in significantly lower concentrations of toxic oligomers (Fig. 4b). The reduction in the population of these species originates from the fact that out of the two processes generating oligomers, primary and secondary nucleation, the chaperone has specifically removed the source that is dominant in Aβ42 aggregation19, namely secondary nucleation (Fig. 6b). It is this ability to turn off the otherwise continuing and increasing generation of oligomers through secondary nucleation that explains the efficacy of this process. It is interesting to note, however, that this reduction in oligomer population occurs even though the eventual quantities of mature fibrils, which are now generated through primary nucleation and elongation alone, remain unaffected by the presence of Brichos19,20.

Bottom Line: Recent studies have revealed that once Aβ42 fibrils are generated, their surfaces effectively catalyze the formation of neurotoxic oligomers.We demonstrate in vitro that Brichos achieves this inhibition by binding to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves minimal formation of toxic oligomeric intermediates.These results reveal that molecular chaperones can help maintain protein homeostasis by selectively suppressing critical microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Cambridge, Cambridge, UK.

ABSTRACT
Alzheimer's disease is an increasingly prevalent neurodegenerative disorder whose pathogenesis has been associated with aggregation of the amyloid-β peptide (Aβ42). Recent studies have revealed that once Aβ42 fibrils are generated, their surfaces effectively catalyze the formation of neurotoxic oligomers. Here we show that a molecular chaperone, a human Brichos domain, can specifically inhibit this catalytic cycle and limit human Aβ42 toxicity. We demonstrate in vitro that Brichos achieves this inhibition by binding to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves minimal formation of toxic oligomeric intermediates. We verify that this mechanism occurs in living mouse brain tissue by cytotoxicity and electrophysiology experiments. These results reveal that molecular chaperones can help maintain protein homeostasis by selectively suppressing critical microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation.

Show MeSH
Related in: MedlinePlus