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

Cohen, Samuel I A ; Arosio, Paolo ; Presto, Jenny ; Kurudenkandy, Firoz Roshan ; Biverstal, Henrik ; Dolfe, Lisa ; Dunning, Christopher ; Yang, Xiaoting ; Frohm, Birgitta ; Vendruscolo, Michele ; Johansson, Jan ; Dobson, Christopher M ; Fisahn, André ; Knowles, Tuomas P J ; Linse, Sara

Nature structural & molecular biology, 2015-03, Vol.22 (3), p.207-213 [Periódico revisado por pares]

United States: Nature Publishing Group

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Título:
A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers
Autor: Cohen, Samuel I A ; Arosio, Paolo ; Presto, Jenny ; Kurudenkandy, Firoz Roshan ; Biverstal, Henrik ; Dolfe, Lisa ; Dunning, Christopher ; Yang, Xiaoting ; Frohm, Birgitta ; Vendruscolo, Michele ; Johansson, Jan ; Dobson, Christopher M ; Fisahn, André ; Knowles, Tuomas P J ; Linse, Sara
Assuntos: Agglomeration ; Alzheimer Disease - metabolism ; Alzheimer's disease ; Amyloid beta-Peptides - metabolism ; Analysis ; Animal tissues ; Animals ; Biochemistry and Molecular Biology ; Biokemi och molekylärbiologi ; Clinical Medicine ; Cryoelectron Microscopy ; Cytotoxicity ; Development and progression ; Electrophysiology ; Female ; Fibrillogenesis ; Health aspects ; Hippocampus - metabolism ; Hippocampus - physiology ; Homeostasis ; Humans ; Intermediates ; Kinetics ; Klinisk medicin ; Male ; Medical and Health Sciences ; Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) ; Medicin och hälsovetenskap ; Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) ; Mice ; Mice, Inbred C57BL ; Molecular chaperones ; Molecular Chaperones - chemistry ; Molecular Chaperones - metabolism ; Molecular Chaperones - physiology ; Neurodegenerative diseases ; Neurologi ; Neurology ; Neurotoxicity ; Oligomers ; Pathogenesis ; Peptides ; Protein Aggregation, Pathological ; Protein Folding ; Protein Structure, Tertiary ; Proteins ; Structure ; Toxic diseases ; Toxicity ; β-Amyloid
É parte de: Nature structural & molecular biology, 2015-03, Vol.22 (3), p.207-213
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Descrição: 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.
Editor: United States: Nature Publishing Group
Idioma: Inglês

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

Cohen, Samuel I A ; Arosio, Paolo ; Presto, Jenny ; Kurudenkandy, Firoz Roshan ; Biverstal, Henrik ; Dolfe, Lisa ; Dunning, Christopher ; Yang, Xiaoting ; Frohm, Birgitta ; Vendruscolo, Michele ; Johansson, Jan ; Dobson, Christopher M ; Fisahn, André ; Knowles, Tuomas P J ; Linse, Sara

United States: Nature Publishing Group

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