Abstract
Objective: Finding a compound that can inhibit glycogen synthesis.
Background: Adult Polyglucosan Body Disease (APBD) is a late-onset disease caused by the intracellular accumulation of polyglucosan bodies, formed due to glycogen branching enzyme (GBE) deficiency. Polyglucosan is similar to glycogen but with fewer branches that precipitates the molecule in the cell and adversely affects the cellular function. Polyglucosan is synthesized by glycogen synthase any compound that inhibit glycogen synthase can be a treatment for Adult polyglucosan body disease or other diseases that are caused by excessive glycogen accumulation.
Design/Methods: We have generated a cell line that is lack of glycogen branching enzyme. This cell line accumulates polyglucosan that can easily be detected and quantified by the automated high throughput systems. We used this mouse embryonic fibroblast cell system to search a compound that can decrease glycogen synthase activity. We have used 1700 FDA-approved drug candidates provided by Johns Hopkins university
Results: High throughput screen discovered that the flavoring agent Guaiacol can lower polyglucosans. Result also confirmed in APBD patient fibroblasts. Biochemical assays using purified muscle glycogen synthase (GYS1) proved that Guaiacol lowers basal and glucose-6-phosphate-stimulated GYS1 activity. In cell lysates, 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 its shorter lifespan. These treatments had no adverse effects except making the mice slightly hypoglycemic, possibly due to the reduced liver glycogen levels. In addition, treatment corrected penile prolapse in aged Gbe1-knockin mice. Interestingly, despite its curative effect, the only organ in which Guaiacol reduced polyglucosan was the liver, which apparently is not pertinent to neurological damage in APBD.
Conclusions: Our results form the basis to use Guaiacol as a treatment and prepare for the clinical trials in APBD.
Background: Adult Polyglucosan Body Disease (APBD) is a late-onset disease caused by the intracellular accumulation of polyglucosan bodies, formed due to glycogen branching enzyme (GBE) deficiency. Polyglucosan is similar to glycogen but with fewer branches that precipitates the molecule in the cell and adversely affects the cellular function. Polyglucosan is synthesized by glycogen synthase any compound that inhibit glycogen synthase can be a treatment for Adult polyglucosan body disease or other diseases that are caused by excessive glycogen accumulation.
Design/Methods: We have generated a cell line that is lack of glycogen branching enzyme. This cell line accumulates polyglucosan that can easily be detected and quantified by the automated high throughput systems. We used this mouse embryonic fibroblast cell system to search a compound that can decrease glycogen synthase activity. We have used 1700 FDA-approved drug candidates provided by Johns Hopkins university
Results: High throughput screen discovered that the flavoring agent Guaiacol can lower polyglucosans. Result also confirmed in APBD patient fibroblasts. Biochemical assays using purified muscle glycogen synthase (GYS1) proved that Guaiacol lowers basal and glucose-6-phosphate-stimulated GYS1 activity. In cell lysates, 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 its shorter lifespan. These treatments had no adverse effects except making the mice slightly hypoglycemic, possibly due to the reduced liver glycogen levels. In addition, treatment corrected penile prolapse in aged Gbe1-knockin mice. Interestingly, despite its curative effect, the only organ in which Guaiacol reduced polyglucosan was the liver, which apparently is not pertinent to neurological damage in APBD.
Conclusions: Our results form the basis to use Guaiacol as a treatment and prepare for the clinical trials in APBD.
| Original language | English |
|---|---|
| Article number | P5.461 |
| Journal | Neurology |
| Volume | 90 |
| Issue number | 15 Supplement |
| State | Published - 9 Apr 2018 |
Bibliographical note
Published By:Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology