A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers.
Author
Summary, in English
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.
Department/s
Publishing year
2015
Language
English
Pages
207-213
Publication/Series
Nature Structural & Molecular Biology
Volume
22
Issue
3
Links
Document type
Journal article
Publisher
Nature Publishing Group
Topic
- Neurology
Status
Published
Research group
- Clinical Memory Research
ISBN/ISSN/Other
- ISSN: 1545-9985