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Interaction of the molecular chaperone DNAJB6 with growing amyloid-beta 42 (Aβ42) aggregates leads to sub-stoichiometric inhibition of amyloid formation.

Månsson, Cecilia LU ; Arosio, Paolo; Hussein, Rasha; Kampinga, Harm H; Hashem, Reem M; Boelens, Wilbert C; Dobson, Christopher M; Knowles, Tuomas P J; Linse, Sara LU and Emanuelsson, Cecilia LU (2014) In Journal of Biological Chemistry 289(45). p.31066-31076
Abstract
The human molecular chaperone protein DNAJB6 was recently found to inhibit the formation of amyloid fibrils from polyglutamine peptides associated with neurodegenerative disorders such as Huntington's disease. We show in the present study that DNAJB6 also inhibits amyloid formation by an even more aggregation-prone peptide (the amyloid-beta peptide, (Aβ42)(2), implicated in Alzheimer's disease)in a highly efficient manner. By monitoring fibril formation using Thioflavin T fluorescence and far-UV CD spectroscopy, we have found that the aggregation of Aβ42 is retarded by DNAJB6 in a concentration dependent manner, extending to very low sub-stoichiometric molar ratios of chaperone to peptide. Quantitative kinetic analysis and immunochemistry... (More)
The human molecular chaperone protein DNAJB6 was recently found to inhibit the formation of amyloid fibrils from polyglutamine peptides associated with neurodegenerative disorders such as Huntington's disease. We show in the present study that DNAJB6 also inhibits amyloid formation by an even more aggregation-prone peptide (the amyloid-beta peptide, (Aβ42)(2), implicated in Alzheimer's disease)in a highly efficient manner. By monitoring fibril formation using Thioflavin T fluorescence and far-UV CD spectroscopy, we have found that the aggregation of Aβ42 is retarded by DNAJB6 in a concentration dependent manner, extending to very low sub-stoichiometric molar ratios of chaperone to peptide. Quantitative kinetic analysis and immunochemistry studies suggest that the high inhibitory efficiency is due to the interactions of the chaperone with aggregated forms of Aβ42 rather than the monomeric form of the peptide. This interaction prevents the growth of such species to longer fibrils and inhibits the formation of new amyloid fibrils through both primary and secondary nucleation. A low dissociation rate of DNAJB6 from Aβ42 aggregates leads to its incorporation into growing fibrils and hence to its gradual depletion from solution with time. When DNAJB6 is eventually depleted, fibril proliferation takes place, but the inhibitory activity can be prolonged by introducing DNAJB6 at regular intervals during the aggregation reaction. These results reveal the highly efficacious mode of action of this molecular chaperone against protein aggregation, and demonstrate that the role of molecular chaperones can involve interactions with multiple aggregated species leading to the inhibition of both principal nucleation pathways through which aggregates are able to form. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
289
issue
45
pages
31066 - 31076
publisher
ASBMB
external identifiers
  • pmid:25217638
  • wos:000344549900016
  • scopus:84909951802
ISSN
1083-351X
DOI
10.1074/jbc.M114.595124
language
English
LU publication?
yes
id
b6266a57-3faa-4616-ab40-053fe985d74d (old id 4691625)
date added to LUP
2014-10-21 22:57:27
date last changed
2017-11-05 03:25:46
@article{b6266a57-3faa-4616-ab40-053fe985d74d,
  abstract     = {The human molecular chaperone protein DNAJB6 was recently found to inhibit the formation of amyloid fibrils from polyglutamine peptides associated with neurodegenerative disorders such as Huntington's disease. We show in the present study that DNAJB6 also inhibits amyloid formation by an even more aggregation-prone peptide (the amyloid-beta peptide, (Aβ42)(2), implicated in Alzheimer's disease)in a highly efficient manner. By monitoring fibril formation using Thioflavin T fluorescence and far-UV CD spectroscopy, we have found that the aggregation of Aβ42 is retarded by DNAJB6 in a concentration dependent manner, extending to very low sub-stoichiometric molar ratios of chaperone to peptide. Quantitative kinetic analysis and immunochemistry studies suggest that the high inhibitory efficiency is due to the interactions of the chaperone with aggregated forms of Aβ42 rather than the monomeric form of the peptide. This interaction prevents the growth of such species to longer fibrils and inhibits the formation of new amyloid fibrils through both primary and secondary nucleation. A low dissociation rate of DNAJB6 from Aβ42 aggregates leads to its incorporation into growing fibrils and hence to its gradual depletion from solution with time. When DNAJB6 is eventually depleted, fibril proliferation takes place, but the inhibitory activity can be prolonged by introducing DNAJB6 at regular intervals during the aggregation reaction. These results reveal the highly efficacious mode of action of this molecular chaperone against protein aggregation, and demonstrate that the role of molecular chaperones can involve interactions with multiple aggregated species leading to the inhibition of both principal nucleation pathways through which aggregates are able to form.},
  author       = {Månsson, Cecilia and Arosio, Paolo and Hussein, Rasha and Kampinga, Harm H and Hashem, Reem M and Boelens, Wilbert C and Dobson, Christopher M and Knowles, Tuomas P J and Linse, Sara and Emanuelsson, Cecilia},
  issn         = {1083-351X},
  language     = {eng},
  number       = {45},
  pages        = {31066--31076},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Interaction of the molecular chaperone DNAJB6 with growing amyloid-beta 42 (Aβ42) aggregates leads to sub-stoichiometric inhibition of amyloid formation.},
  url          = {http://dx.doi.org/10.1074/jbc.M114.595124},
  volume       = {289},
  year         = {2014},
}