Isoform-selective Hsp90 inhibition rescues model of hereditary open-angle glaucoma

  • Sci Rep. 2017 Dec 20;7(1):17951. doi: 10.1038/s41598-017-18344-4.
Andrew R Stothert  1 ,  Amirthaa Suntharalingam  1 ,  Xiaolan Tang  1  2 ,  Vincent M Crowley  3 ,  Sanket J Mishra  3 ,  Jack M Webster  1 ,  Bryce A Nordhues  1 ,  Dustin J E Huard  4 ,  Christopher L Passaglia  2 ,  Raquel L Lieberman  4 ,  Brian S J Blagg  3 ,  Laura J Blair  5 ,  John Koren 3rd  6 ,  Chad A Dickey  1
Affiliations
  • 1. Department of Molecular Medicine and Byrd Alzheimer's Research Institute, University of South Florida, Tampa, FL, 33613, USA.
  • 2. Department of Chemical & Biomedical Engineering, College of Engineering, University of South Florida, Tampa, FL, 33613, USA.
  • 3. Department of Medicinal Chemistry, The University of Kansas, Lawrence, KS, 66045, USA.
  • 4. School of Chemistry & Biochemistry, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
  • 5. Department of Molecular Medicine and Byrd Alzheimer's Research Institute, University of South Florida, Tampa, FL, 33613, USA. [email protected].
  • 6. Department of Molecular Medicine and Byrd Alzheimer's Research Institute, University of South Florida, Tampa, FL, 33613, USA. [email protected].
PMID: 29263415 DOI: 10.1038/s41598-017-18344-4
Abstract

The heat shock protein 90 (HSP90) family of molecular chaperones regulates protein homeostasis, folding, and degradation. The ER-resident HSP90 isoform, glucose-regulated protein 94 (Grp94), promotes the aggregation of mutant forms of myocilin, a protein associated with primary open-angle glaucoma. While inhibition of Grp94 promotes the degradation of mutant myocilin in vitro, to date no Grp94-selective inhibitors have been investigated in vivo. Here, a Grp94-selective inhibitor facilitated mutant myocilin degradation and rescued phenotypes in a transgenic mouse model of hereditary primary open-angle glaucoma. Ocular toxicities previously associated with pan-Hsp90 inhibitors were not evident with our Grp94-selective inhibitor, 4-Br-BnIm. Our study suggests that selective inhibition of a distinct HSP90 family member holds translational promise for ocular and Other Diseases associated with cell stress and protein misfolding.

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