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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4691625
- author
- 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
- organization
- publishing date
- 2014
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 289
- issue
- 45
- pages
- 31066 - 31076
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- pmid:25217638
- wos:000344549900016
- scopus:84909951802
- pmid:25217638
- 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
- 2016-04-01 11:11:51
- date last changed
- 2022-04-20 17:39:30
@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 = {{American Society for Biochemistry and Molecular Biology}},
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}},
doi = {{10.1074/jbc.M114.595124}},
volume = {{289}},
year = {{2014}},
}