Journal Article

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

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

2015

Overview

Aβ peptide aggregation is associated with Alzheimer's disease, and Aβ fibrils can catalyze formation of toxic oligomers. Molecular chaperone Brichos binds to the fibril surface, inhibiting the catalytic cycle in vitro , and limits Aβ toxicity. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/57/2272/1590 / 631/57/2272/2276 / Agglomeration / Alzheimer Disease - metabolism / Alzheimer's disease / Amyloid beta-Peptides - metabolism / Analysis / Animal tissues / Animals / Biochemistry / Biochemistry and Molecular Biology / Biokemi och molekylärbiologi / Biological Microscopy / Clinical Medicine / Cryoelectron Microscopy / Cytotoxicity / Development and progression / Electrophysiology / Female / Fibrillogenesis / Health aspects / Hippocampus - metabolism / Hippocampus - physiology / Homeostasis / Humans / Intermediates / Kinetics / Klinisk medicin / Life Sciences / 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) / Membrane Biology / 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 / Protein Structure, Tertiary / Proteins / Structure / Toxic diseases / Toxicity / β-Amyloid