Document Type

Article

Publication Date

6-19-2019

Keywords

JMG

JAX Source

ACS Chem Neurosci 2019 Jun 19; 10(6):2890-2902

Volume

10

Issue

6

First Page

2890

Last Page

2902

ISSN

1948-7193

PMID

31017387

DOI

https://doi.org/10.1021/acschemneuro.9b00105

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.

Comments

This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

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