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The small heat shock protein Hsp27 binds α-synuclein fibrils, preventing elongation and cytotoxicity

Journal Article


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Abstract


  • Proteostasis, or protein homeostasis, encompasses the maintenance of the conformational and functional integrity of the proteome and involves an integrated network of cellular pathways. Molecular chaperones, such as the small heat shock proteins (sHsps), are key elements of the proteostasis network that have crucial roles in inhibiting the aggregation of misfolded proteins. Failure of the proteostasis network can lead to the accumulation of misfolded proteins into intracellular and extracellular deposits. Deposits containing fibrillar forms of α-sy-nuclein (α-syn) are characteristic of neurodegenerative disorders including Parkinson’s disease and dementia with Lewy bodies. Here we show that the sHsp Hsp27 (HSPB1) binds to α-syn fibrils, inhibiting fibril growth by preventing elongation. Using total internal reflection fluorescence (TIRF)– based imaging methods, we show that Hsp27 binds along the surface of α-syn fibrils, decreasing their hydrophobicity. Binding of Hsp27 also inhibits cytotoxicity of α-syn fibrils. Our results demonstrate that the ability of sHsps, such as Hsp27, to bind fibrils represents an important mechanism through which they May mitigate cellular toxicity associated with aberrant protein aggregation. Fibril binding May represent a generic mechanism by which chaperone-active sHsps interact with aggregation-prone proteins, highlighting the potential to target sHsp activity to prevent or disrupt the onset and progression of α-syn aggregation associated with α-synucleinopathies.

Authors


  •   Cox, Dezerae (external author)
  •   Whiten, Daniel (external author)
  •   Brown, James W. P. (external author)
  •   Horrocks, Mathew H. (external author)
  •   San Gil, Rebecca (external author)
  •   Dobson, Christopher M. (external author)
  •   Klenerman, David (external author)
  •   van Oijen, Antoine M.
  •   Ecroyd, Heath

Publication Date


  • 2018

Citation


  • Cox, D., Whiten, D. R., Brown, J. W. P., Horrocks, M. H., San Gil, R., Dobson, C. M., Klenerman, D., van Oijen, A. M. & Ecroyd, H. (2018). The small heat shock protein Hsp27 binds α-synuclein fibrils, preventing elongation and cytotoxicity. Journal of Biological Chemistry, 293 (12), 4486-4497.

Scopus Eid


  • 2-s2.0-85044404789

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2251&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1224

Number Of Pages


  • 11

Start Page


  • 4486

End Page


  • 4497

Volume


  • 293

Issue


  • 12

Place Of Publication


  • United States

Abstract


  • Proteostasis, or protein homeostasis, encompasses the maintenance of the conformational and functional integrity of the proteome and involves an integrated network of cellular pathways. Molecular chaperones, such as the small heat shock proteins (sHsps), are key elements of the proteostasis network that have crucial roles in inhibiting the aggregation of misfolded proteins. Failure of the proteostasis network can lead to the accumulation of misfolded proteins into intracellular and extracellular deposits. Deposits containing fibrillar forms of α-sy-nuclein (α-syn) are characteristic of neurodegenerative disorders including Parkinson’s disease and dementia with Lewy bodies. Here we show that the sHsp Hsp27 (HSPB1) binds to α-syn fibrils, inhibiting fibril growth by preventing elongation. Using total internal reflection fluorescence (TIRF)– based imaging methods, we show that Hsp27 binds along the surface of α-syn fibrils, decreasing their hydrophobicity. Binding of Hsp27 also inhibits cytotoxicity of α-syn fibrils. Our results demonstrate that the ability of sHsps, such as Hsp27, to bind fibrils represents an important mechanism through which they May mitigate cellular toxicity associated with aberrant protein aggregation. Fibril binding May represent a generic mechanism by which chaperone-active sHsps interact with aggregation-prone proteins, highlighting the potential to target sHsp activity to prevent or disrupt the onset and progression of α-syn aggregation associated with α-synucleinopathies.

Authors


  •   Cox, Dezerae (external author)
  •   Whiten, Daniel (external author)
  •   Brown, James W. P. (external author)
  •   Horrocks, Mathew H. (external author)
  •   San Gil, Rebecca (external author)
  •   Dobson, Christopher M. (external author)
  •   Klenerman, David (external author)
  •   van Oijen, Antoine M.
  •   Ecroyd, Heath

Publication Date


  • 2018

Citation


  • Cox, D., Whiten, D. R., Brown, J. W. P., Horrocks, M. H., San Gil, R., Dobson, C. M., Klenerman, D., van Oijen, A. M. & Ecroyd, H. (2018). The small heat shock protein Hsp27 binds α-synuclein fibrils, preventing elongation and cytotoxicity. Journal of Biological Chemistry, 293 (12), 4486-4497.

Scopus Eid


  • 2-s2.0-85044404789

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2251&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1224

Number Of Pages


  • 11

Start Page


  • 4486

End Page


  • 4497

Volume


  • 293

Issue


  • 12

Place Of Publication


  • United States