Advanced

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

Cohen, Samuel I A; Arosio, Paolo; Presto, Jenny; Kurudenkandy, Firoz Roshan; Biverstål, Henrik; Dolfe, Lisa; Dunning, Christopher LU ; Yang, Xiaoting; Frohm, Birgitta and Vendruscolo, Michele, et al. (2015) In Nature Structural & Molecular Biology 22(3). p.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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Structural & Molecular Biology
volume
22
issue
3
pages
207 - 213
publisher
Nature Publishing Group
external identifiers
  • pmid:25686087
  • wos:000350531000009
  • scopus:84924196173
ISSN
1545-9985
DOI
10.1038/nsmb.2971
language
English
LU publication?
yes
id
30a97378-e770-4e29-8a9d-847088245d1c (old id 5143557)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25686087?dopt=Abstract
date added to LUP
2015-03-08 17:32:12
date last changed
2017-11-12 03:01:05
@article{30a97378-e770-4e29-8a9d-847088245d1c,
  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.},
  author       = {Cohen, Samuel I A and Arosio, Paolo and Presto, Jenny and Kurudenkandy, Firoz Roshan and Biverstål, Henrik and Dolfe, Lisa and Dunning, Christopher and Yang, Xiaoting and Frohm, Birgitta and Vendruscolo, Michele and Johansson, Jan and Dobson, Christopher M and Fisahn, André and Knowles, Tuomas P J and Linse, Sara},
  issn         = {1545-9985},
  language     = {eng},
  number       = {3},
  pages        = {207--213},
  publisher    = {Nature Publishing Group},
  series       = {Nature Structural & Molecular Biology},
  title        = {A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers.},
  url          = {http://dx.doi.org/10.1038/nsmb.2971},
  volume       = {22},
  year         = {2015},
}