A novel image-based high-throughput screening assay discovers therapeutic candidates for adult polyglucosan body disease

Leonardo J. Solmesky, Netaly Khazanov, Hanoch Senderowitz, Peixiang Wang, Berge A. Minassian, Igor M. Ferreira, Wyatt W. Yue, Alexander Lossos, Miguel Weil*, Or Kakhlon

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Glycogen storage disorders (GSDs) are caused by excessive accumulation of glycogen. Some GSDs [adult polyglucosan (PG) body disease (APBD), and Tarui and Lafora diseases] are caused by intracellular accumulation of insoluble inclusions, called PG bodies (PBs), which are chiefly composed of malconstructed glycogen. We developed an APBD patient skin fibroblast cell-based assay for PB identification, where the bodies are identified as amylase-resistant periodic acid–Schiff’s-stained structures, and quantified. We screened the DIVERSet CL 10 084 compound library using this assay in high-throughput format and discovered 11 dose-dependent and 8 non-dose-dependent PB-reducing hits. Approximately 70% of the hits appear to act through reducing glycogen synthase (GS) activity, which can elongate glycogen chains and presumably promote PB generation. Some of these GS inhibiting hits were also computationally predicted to be similar to drugs interacting with the GS activator protein phosphatase 1. Our work paves the way to discovering medications for the treatment of PB-involving GSD, which are extremely severe or fatal disorders.

Original languageAmerican English
Pages (from-to)3403-3420
Number of pages18
JournalBiochemical Journal
Issue number20
StatePublished - 15 Oct 2017
Externally publishedYes

Bibliographical note

Funding Information:
This work was made possible thanks to grants from the Association Francaise contre les Myopathies (AFM) [grant number 16171] and the APBD Research Foundation (both to O.K.). L.J.S. was supported by funds from the Cell Screening Facility for Personalized Medicine (CSFPM), Tel Aviv University. B.A.M. was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NIH) under award number P01 NS097197, the Ontario Brain Institute, the University of Toronto Michael Bahen Chair in Epilepsy Research, and the University of Texas Southwestern Jimmy Elizabeth Wescott Chair in Pediatric Neurology.

Publisher Copyright:
© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.


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