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The cysteine-reactive small molecule ebselen facilitates effective SOD1 maturation

Journal Article


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Abstract


  • Superoxide dismutase-1 (SOD1) mutants, including those with unaltered enzymatic activity, are known to cause amyotrophic lateral sclerosis (ALS). Several destabilizing factors contribute to pathogenicity including a reduced ability to complete the normal maturation process which comprises folding, metal cofactor acquisition, intra-subunit disulphide bond formation and dimerization. Immature SOD1 forms toxic oligomers and characteristic large insoluble aggregates within motor system cells. Here we report that the cysteine-reactive molecule ebselen efficiently confers the SOD1 intra-subunit disulphide and directs correct SOD1 folding, depopulating the globally unfolded precursor associated with aggregation and toxicity. Assisted formation of the unusual SOD1 cytosolic disulphide bond could have potential therapeutic applications. In less reducing environments, ebselen forms a selenylsulphide with Cys111 and restores the monomer-dimer equilibrium of A4V SOD1 to wild-type. Ebselen is therefore a potent bifunctional pharmacological chaperone for SOD1 that combines properties of the SOD1 chaperone hCCS and the recently licenced antioxidant drug, edaravone.

Authors


  •   Capper, Michael J. (external author)
  •   Wright, Gareth S. A. (external author)
  •   Barbieri, Letizia (external author)
  •   Luchinat, Enrico (external author)
  •   Mercatelli, Eleonora (external author)
  •   McAlary, Luke
  •   Yerbury, Justin J.
  •   O'Neill, Paul M. (external author)
  •   Antonyuk, Svetlana V. (external author)
  •   Banci, Lucia (external author)
  •   Hasnain, S Samar. (external author)

Publication Date


  • 2018

Citation


  • Capper, M. J., Wright, G. S. A., Barbieri, L., Luchinat, E., Mercatelli, E., McAlary, L., Yerbury, J. J., O'Neill, P. M., Antonyuk, S. V., Banci, L. & Hasnain, S. Samar. (2018). The cysteine-reactive small molecule ebselen facilitates effective SOD1 maturation. Nature Communications, 9 (1), 1693-1-1693-9.

Scopus Eid


  • 2-s2.0-85046149452

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=6581&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/5516

Start Page


  • 1693-1

End Page


  • 1693-9

Volume


  • 9

Issue


  • 1

Place Of Publication


  • United Kingdom

Abstract


  • Superoxide dismutase-1 (SOD1) mutants, including those with unaltered enzymatic activity, are known to cause amyotrophic lateral sclerosis (ALS). Several destabilizing factors contribute to pathogenicity including a reduced ability to complete the normal maturation process which comprises folding, metal cofactor acquisition, intra-subunit disulphide bond formation and dimerization. Immature SOD1 forms toxic oligomers and characteristic large insoluble aggregates within motor system cells. Here we report that the cysteine-reactive molecule ebselen efficiently confers the SOD1 intra-subunit disulphide and directs correct SOD1 folding, depopulating the globally unfolded precursor associated with aggregation and toxicity. Assisted formation of the unusual SOD1 cytosolic disulphide bond could have potential therapeutic applications. In less reducing environments, ebselen forms a selenylsulphide with Cys111 and restores the monomer-dimer equilibrium of A4V SOD1 to wild-type. Ebselen is therefore a potent bifunctional pharmacological chaperone for SOD1 that combines properties of the SOD1 chaperone hCCS and the recently licenced antioxidant drug, edaravone.

Authors


  •   Capper, Michael J. (external author)
  •   Wright, Gareth S. A. (external author)
  •   Barbieri, Letizia (external author)
  •   Luchinat, Enrico (external author)
  •   Mercatelli, Eleonora (external author)
  •   McAlary, Luke
  •   Yerbury, Justin J.
  •   O'Neill, Paul M. (external author)
  •   Antonyuk, Svetlana V. (external author)
  •   Banci, Lucia (external author)
  •   Hasnain, S Samar. (external author)

Publication Date


  • 2018

Citation


  • Capper, M. J., Wright, G. S. A., Barbieri, L., Luchinat, E., Mercatelli, E., McAlary, L., Yerbury, J. J., O'Neill, P. M., Antonyuk, S. V., Banci, L. & Hasnain, S. Samar. (2018). The cysteine-reactive small molecule ebselen facilitates effective SOD1 maturation. Nature Communications, 9 (1), 1693-1-1693-9.

Scopus Eid


  • 2-s2.0-85046149452

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=6581&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/5516

Start Page


  • 1693-1

End Page


  • 1693-9

Volume


  • 9

Issue


  • 1

Place Of Publication


  • United Kingdom