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Guaiacol as a drug candidate for treating adult polyglucosan body disease
Or Kakhlon, … , Wyatt W. Yue, H. Orhan Akman
Or Kakhlon, … , Wyatt W. Yue, H. Orhan Akman
Published September 6, 2018
Citation Information: JCI Insight. 2018;3(17):e99694. https://doi.org/10.1172/jci.insight.99694.
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Research Article Metabolism Therapeutics

Guaiacol as a drug candidate for treating adult polyglucosan body disease

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Abstract

Adult polyglucosan body disease (APBD) is a late-onset disease caused by intracellular accumulation of polyglucosan bodies, formed due to glycogen-branching enzyme (GBE) deficiency. To find a treatment for APBD, we screened 1,700 FDA-approved compounds in fibroblasts derived from APBD-modeling GBE1-knockin mice. Capitalizing on fluorescent periodic acid–Schiff reagent, which interacts with polyglucosans in the cell, this screen discovered that the flavoring agent guaiacol can lower polyglucosans, a result also confirmed in APBD patient fibroblasts. Biochemical assays showed that guaiacol lowers basal and glucose 6-phosphate–stimulated glycogen synthase (GYS) activity. Guaiacol also increased inactivating GYS1 phosphorylation and phosphorylation of the master activator of catabolism, AMP-dependent protein kinase. Guaiacol treatment in the APBD mouse model rescued grip strength and shorter lifespan. These treatments had no adverse effects except making the mice slightly hyperglycemic, possibly due to the reduced liver glycogen levels. In addition, treatment corrected penile prolapse in aged GBE1-knockin mice. Guaiacol’s curative effects can be explained by its reduction of polyglucosans in peripheral nerve, liver, and heart, despite a short half-life of up to 60 minutes in most tissues. Our results form the basis to use guaiacol as a treatment and prepare for the clinical trials in APBD.

Authors

Or Kakhlon, Igor Ferreira, Leonardo J. Solmesky, Netaly Khazanov, Alexander Lossos, Rafael Alvarez, Deniz Yetil, Sergey Pampou, Miguel Weil, Hanoch Senderowitz, Pablo Escriba, Wyatt W. Yue, H. Orhan Akman

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Figure 1

Diastase-resistant PAS-positive accumulations in GBE1neo/– mouse embryonic fibroblasts (MEFs) are detectable by light microscopy as well as fluorescence microscopy.

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Diastase-resistant PAS-positive accumulations in GBE1neo/– mouse embryon...
(A) GBE1+/+ cells do not exhibit periodic acid–Schiff–positive (PAS-positive) staining in the cytosol. (B) GBE1neo/– fibroblasts accumulate polyglucosan bodies (PGBs), indicated by arrowheads (×600 magnification). (C and D) PAS-stained control MEFs with lower magnification (×200) and fluorescence image of the same field. (E and F) The same imaging technique was used to detect PGBs (black and yellow arrowheads) in GBE1neo/– MEFs. (G and H) Digital magnifications of the outlined fields in E and F showing large round PGBs. Scales of each image are indicated in the bottom right corner. Representative images out of hundreds taken during the HTS campaign.

Copyright © 2021 American Society for Clinical Investigation
ISSN 2379-3708

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