Publication

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

Månsson, C., Arosio, P., Hussein, R., Kampinga, H. H., Hashem, R. M., Boelens, W. C., Dobson, C. M., Knowles, T. P. J., Linse, S. & Emanuelsson, C., 7-Nov-2014, In : The Journal of Biological Chemistry. 289, 45, p. 31066-31076 11 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Månsson, C., Arosio, P., Hussein, R., Kampinga, H. H., Hashem, R. M., Boelens, W. C., Dobson, C. M., Knowles, T. P. J., Linse, S., & Emanuelsson, C. (2014). Interaction of the molecular chaperone DNAJB6 with growing amyloid-beta 42 (Aβ42) aggregates leads to sub-stoichiometric inhibition of amyloid formation. The Journal of Biological Chemistry, 289(45), 31066-31076. https://doi.org/10.1074/jbc.M114.595124

Author

Månsson, Cecilia ; Arosio, Paolo ; Hussein, Rasha ; Kampinga, Harm H ; Hashem, Reem M ; Boelens, Wilbert C ; Dobson, Christopher M ; Knowles, Tuomas P J ; Linse, Sara ; Emanuelsson, Cecilia. / Interaction of the molecular chaperone DNAJB6 with growing amyloid-beta 42 (Aβ42) aggregates leads to sub-stoichiometric inhibition of amyloid formation. In: The Journal of Biological Chemistry. 2014 ; Vol. 289, No. 45. pp. 31066-31076.

Harvard

Månsson, C, Arosio, P, Hussein, R, Kampinga, HH, Hashem, RM, Boelens, WC, Dobson, CM, Knowles, TPJ, Linse, S & Emanuelsson, C 2014, 'Interaction of the molecular chaperone DNAJB6 with growing amyloid-beta 42 (Aβ42) aggregates leads to sub-stoichiometric inhibition of amyloid formation', The Journal of Biological Chemistry, vol. 289, no. 45, pp. 31066-31076. https://doi.org/10.1074/jbc.M114.595124

Standard

Interaction of the molecular chaperone DNAJB6 with growing amyloid-beta 42 (Aβ42) aggregates leads to sub-stoichiometric inhibition of amyloid formation. / Månsson, Cecilia; Arosio, Paolo; Hussein, Rasha; Kampinga, Harm H; Hashem, Reem M; Boelens, Wilbert C; Dobson, Christopher M; Knowles, Tuomas P J; Linse, Sara; Emanuelsson, Cecilia.

In: The Journal of Biological Chemistry, Vol. 289, No. 45, 07.11.2014, p. 31066-31076.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Månsson C, Arosio P, Hussein R, Kampinga HH, Hashem RM, Boelens WC et al. Interaction of the molecular chaperone DNAJB6 with growing amyloid-beta 42 (Aβ42) aggregates leads to sub-stoichiometric inhibition of amyloid formation. The Journal of Biological Chemistry. 2014 Nov 7;289(45):31066-31076. https://doi.org/10.1074/jbc.M114.595124


BibTeX

@article{d3512701492543ecb56e9d5fa7ab3158,
title = "Interaction of the molecular chaperone DNAJB6 with growing amyloid-beta 42 (Aβ42) aggregates leads to sub-stoichiometric inhibition of amyloid formation",
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.",
keywords = "ALPHA-B-CRYSTALLIN, PROTEIN AGGREGATION, ALZHEIMERS-DISEASE, POLYGLUTAMINE PEPTIDES, NUCLEATION MECHANISM, COMMON MECHANISM, OLIGOMERS, KINETICS, TOXICITY, BINDING",
author = "Cecilia M{\aa}nsson and Paolo Arosio and Rasha Hussein and Kampinga, {Harm H} and Hashem, {Reem M} and Boelens, {Wilbert C} and Dobson, {Christopher M} and Knowles, {Tuomas P J} and Sara Linse and Cecilia Emanuelsson",
note = "Copyright {\textcopyright} 2014, The American Society for Biochemistry and Molecular Biology.",
year = "2014",
month = nov,
day = "7",
doi = "10.1074/jbc.M114.595124",
language = "English",
volume = "289",
pages = "31066--31076",
journal = "The Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC",
number = "45",

}

RIS

TY - JOUR

T1 - Interaction of the molecular chaperone DNAJB6 with growing amyloid-beta 42 (Aβ42) aggregates leads to sub-stoichiometric inhibition of amyloid formation

AU - Månsson, Cecilia

AU - Arosio, Paolo

AU - Hussein, Rasha

AU - Kampinga, Harm H

AU - Hashem, Reem M

AU - Boelens, Wilbert C

AU - Dobson, Christopher M

AU - Knowles, Tuomas P J

AU - Linse, Sara

AU - Emanuelsson, Cecilia

N1 - Copyright © 2014, The American Society for Biochemistry and Molecular Biology.

PY - 2014/11/7

Y1 - 2014/11/7

N2 - 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.

AB - 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.

KW - ALPHA-B-CRYSTALLIN

KW - PROTEIN AGGREGATION

KW - ALZHEIMERS-DISEASE

KW - POLYGLUTAMINE PEPTIDES

KW - NUCLEATION MECHANISM

KW - COMMON MECHANISM

KW - OLIGOMERS

KW - KINETICS

KW - TOXICITY

KW - BINDING

U2 - 10.1074/jbc.M114.595124

DO - 10.1074/jbc.M114.595124

M3 - Article

C2 - 25217638

VL - 289

SP - 31066

EP - 31076

JO - The Journal of Biological Chemistry

JF - The Journal of Biological Chemistry

SN - 0021-9258

IS - 45

ER -

ID: 14138766