2. Academic Validation
  3. Isoform-selective Hsp90 inhibition rescues model of hereditary open-angle glaucoma

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

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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