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HSP90 Inhibitor, NVP-AUY922, Improves Myelination in Vitro and Supports the Maintenance of Myelinated Axons in Neuropathic Mice.

Authors
  • Chittoor-Vinod, Vinita G1
  • Bazick, Hannah1
  • Todd, Adrian G2
  • Falk, Darin2
  • Morelli, Kathryn H3, 4
  • Burgess, Robert W3, 4
  • Foster, Thomas C1
  • Notterpek, Lucia1
  • 1 Departments of Neuroscience and Neurology, College of Medicine , McKnight Brain Institute , 1149 Newell Drive , Box 100244, Gainesville , Florida 32610-0244 , United States. , (United States)
  • 2 Department of Pediatrics, Powell Gene Therapy Center , University of Florida , Gainesville , Florida 32611 , United States. , (United States)
  • 3 The Graduate School of Biomedical Science and Engineering , University of Maine , Orono , Maine 04469 , United States. , (United States)
  • 4 The Jackson Laboratory , Bar Harbor , Maine 04609 , United States. , (United States)
Type
Published Article
Journal
ACS Chemical Neuroscience
Publisher
American Chemical Society
Publication Date
Jun 19, 2019
Volume
10
Issue
6
Pages
2890–2902
Identifiers
DOI: 10.1021/acschemneuro.9b00105
PMID: 31017387
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Hereditary demyelinating neuropathies linked to peripheral myelin protein 22 (PMP22) involve the disruption of normal protein trafficking and are therefore relevant targets for chaperone therapy. Using a small molecule HSP90 inhibitor, EC137, in cell culture models, we previously validated the chaperone pathway as a viable target for therapy development. Here, we tested five commercially available inhibitors of HSP90 and identified BIIB021 and AUY922 to support Schwann cell viability and enhance chaperone expression. AUY922 showed higher efficacy, compared to BIIB021, in enhancing myelin synthesis in dorsal root ganglion explant cultures from neuropathic mice. For in vivo testing, we randomly assigned 2-3 month old C22 and 6 week old Trembler J (TrJ) mice to receive two weekly injections of either vehicle or AUY922 (2 mg/kg). By the intraperitoneal (i.p.) route, the drug was well-tolerated by all mice over the 5 month long study, without influence on body weight or general grooming behavior. AUY922 improved the maintenance of myelinated nerves of both neuropathic models and attenuated the decline in rotarod performance and peak muscle force production in C22 mice. These studies highlight the significance of proteostasis in neuromuscular function and further validate the HSP90 pathway as a therapeutic target for hereditary neuropathies.

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