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Small heat-shock proteins prevent a-synuclein aggregation via transient interactions and their efficacy is affected by the rate of aggregation

Journal Article


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Abstract


  • The aggregation of a-synuclein (a-syn) into amyloid fibrils is associated with neurodegenerative diseases, collectively referred to as the a-synucleinopathies. In vivo, molecular chaperones, such as the small heat-shock proteins (sHsps), normally act to prevent protein aggregation; however, it remains to be determined how aggregation-prone a-syn evades sHsp chaperone action leading to its disease-associated deposition. This work examines the molecular mechanism by which two canonical sHsps, aB-crystallin (aB-c) and Hsp27, interact with aggregation-prone a-syn to prevent its aggregation in vitro. Both sHsps are very effective inhibitors of ¿-syn aggregation, but no stable complex between the sHsps and a-syn was detected, indicating that the sHsps inhibit a-syn aggregation via transient interactions. Moreover, the ability of these sHsps to prevent a-syn aggregation was dependent on the kinetics of aggregation; the faster the rate of aggregation (shorter the lag phase), the less effective the sHsps were at inhibiting fibril formation of a-syn. Thus, these findings indicate that the rate at which a-syn aggregates in cells may be a significant factor in how it evades sHsp chaperone action in the a-synucleinopathies.

Authors


  •   Cox, Dezerae (external author)
  •   Selig, Emily (external author)
  •   Griffin, Michael D. W. (external author)
  •   Carver, John A. (external author)
  •   Ecroyd, Heath

Publication Date


  • 2016

Citation


  • Cox, D., Selig, E., Griffin, M. D. W., Carver, J. A. & Ecroyd, H. (2016). Small heat-shock proteins prevent a-synuclein aggregation via transient interactions and their efficacy is affected by the rate of aggregation. Journal of Biological Chemistry, 291 (43), 22618-22629.

Scopus Eid


  • 2-s2.0-84992316267

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1955&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/930

Has Global Citation Frequency


Number Of Pages


  • 11

Start Page


  • 22618

End Page


  • 22629

Volume


  • 291

Issue


  • 43

Place Of Publication


  • United States

Abstract


  • The aggregation of a-synuclein (a-syn) into amyloid fibrils is associated with neurodegenerative diseases, collectively referred to as the a-synucleinopathies. In vivo, molecular chaperones, such as the small heat-shock proteins (sHsps), normally act to prevent protein aggregation; however, it remains to be determined how aggregation-prone a-syn evades sHsp chaperone action leading to its disease-associated deposition. This work examines the molecular mechanism by which two canonical sHsps, aB-crystallin (aB-c) and Hsp27, interact with aggregation-prone a-syn to prevent its aggregation in vitro. Both sHsps are very effective inhibitors of ¿-syn aggregation, but no stable complex between the sHsps and a-syn was detected, indicating that the sHsps inhibit a-syn aggregation via transient interactions. Moreover, the ability of these sHsps to prevent a-syn aggregation was dependent on the kinetics of aggregation; the faster the rate of aggregation (shorter the lag phase), the less effective the sHsps were at inhibiting fibril formation of a-syn. Thus, these findings indicate that the rate at which a-syn aggregates in cells may be a significant factor in how it evades sHsp chaperone action in the a-synucleinopathies.

Authors


  •   Cox, Dezerae (external author)
  •   Selig, Emily (external author)
  •   Griffin, Michael D. W. (external author)
  •   Carver, John A. (external author)
  •   Ecroyd, Heath

Publication Date


  • 2016

Citation


  • Cox, D., Selig, E., Griffin, M. D. W., Carver, J. A. & Ecroyd, H. (2016). Small heat-shock proteins prevent a-synuclein aggregation via transient interactions and their efficacy is affected by the rate of aggregation. Journal of Biological Chemistry, 291 (43), 22618-22629.

Scopus Eid


  • 2-s2.0-84992316267

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1955&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/930

Has Global Citation Frequency


Number Of Pages


  • 11

Start Page


  • 22618

End Page


  • 22629

Volume


  • 291

Issue


  • 43

Place Of Publication


  • United States