PMID:25686087

Citation	Cohen, SIA, Arosio, P, Presto, J, Kurudenkandy, FR, Biverstal, H, Dolfe, L, Dunning, C, Yang, X, Frohm, B, Vendruscolo, M, Johansson, J, Dobson, CM, Fisahn, A, Knowles, TPJ and Linse, S (2015) A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers. Nat. Struct. Mol. Biol. 22:207-213
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.
Links	PubMed PMC4595974 Online version:10.1038/nsmb.2971
Keywords	Alzheimer Disease/metabolism; Amyloid beta-Peptides/metabolism; Animals; Cryoelectron Microscopy; Electrophysiology; Female; Hippocampus/metabolism; Hippocampus/physiology; Humans; Kinetics; Male; Mice; Mice, Inbred C57BL; Molecular Chaperones/chemistry; Molecular Chaperones/metabolism; Molecular Chaperones/physiology; Protein Aggregation, Pathological; Protein Folding; Protein Structure, Tertiary
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:A4	enables	GO:0042802: identical protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:P05067:PRO_0000000092	F		Seeded From UniProt	complete

References

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