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

[Image: see text] 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 v...

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Autores principales: Chittoor-Vinod, Vinita G., Bazick, Hannah, Todd, Adrian G., Falk, Darin, Morelli, Kathryn H., Burgess, Robert W., Foster, Thomas C., Notterpek, Lucia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2019
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588339/
https://www.ncbi.nlm.nih.gov/pubmed/31017387
http://dx.doi.org/10.1021/acschemneuro.9b00105
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author Chittoor-Vinod, Vinita G.
Bazick, Hannah
Todd, Adrian G.
Falk, Darin
Morelli, Kathryn H.
Burgess, Robert W.
Foster, Thomas C.
Notterpek, Lucia
author_facet Chittoor-Vinod, Vinita G.
Bazick, Hannah
Todd, Adrian G.
Falk, Darin
Morelli, Kathryn H.
Burgess, Robert W.
Foster, Thomas C.
Notterpek, Lucia
author_sort Chittoor-Vinod, Vinita G.
collection PubMed
description [Image: see text] 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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spelling pubmed-65883392019-06-24 HSP90 Inhibitor, NVP-AUY922, Improves Myelination in Vitro and Supports the Maintenance of Myelinated Axons in Neuropathic Mice Chittoor-Vinod, Vinita G. Bazick, Hannah Todd, Adrian G. Falk, Darin Morelli, Kathryn H. Burgess, Robert W. Foster, Thomas C. Notterpek, Lucia ACS Chem Neurosci [Image: see text] 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. American Chemical Society 2019-04-24 /pmc/articles/PMC6588339/ /pubmed/31017387 http://dx.doi.org/10.1021/acschemneuro.9b00105 Text en Copyright © 2019 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Chittoor-Vinod, Vinita G.
Bazick, Hannah
Todd, Adrian G.
Falk, Darin
Morelli, Kathryn H.
Burgess, Robert W.
Foster, Thomas C.
Notterpek, Lucia
HSP90 Inhibitor, NVP-AUY922, Improves Myelination in Vitro and Supports the Maintenance of Myelinated Axons in Neuropathic Mice
title HSP90 Inhibitor, NVP-AUY922, Improves Myelination in Vitro and Supports the Maintenance of Myelinated Axons in Neuropathic Mice
title_full HSP90 Inhibitor, NVP-AUY922, Improves Myelination in Vitro and Supports the Maintenance of Myelinated Axons in Neuropathic Mice
title_fullStr HSP90 Inhibitor, NVP-AUY922, Improves Myelination in Vitro and Supports the Maintenance of Myelinated Axons in Neuropathic Mice
title_full_unstemmed HSP90 Inhibitor, NVP-AUY922, Improves Myelination in Vitro and Supports the Maintenance of Myelinated Axons in Neuropathic Mice
title_short HSP90 Inhibitor, NVP-AUY922, Improves Myelination in Vitro and Supports the Maintenance of Myelinated Axons in Neuropathic Mice
title_sort hsp90 inhibitor, nvp-auy922, improves myelination in vitro and supports the maintenance of myelinated axons in neuropathic mice
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588339/
https://www.ncbi.nlm.nih.gov/pubmed/31017387
http://dx.doi.org/10.1021/acschemneuro.9b00105
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