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

9 Scopus citations

Abstract

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 languageEnglish
Pages (from-to)3403-3420
Number of pages18
JournalBiochemical Journal
Volume474
Issue number20
DOIs
StatePublished - 15 Oct 2017

Funding

FundersFunder number
APBD Research Foundation
Cell Screening Facility for Personalized Medicine
University of Texas Southwestern Jimmy Elizabeth Wescott Chair in Pediatric Neurology
National Institutes of Health
National Institute of Neurological Disorders and StrokeP01NS097197
Association Française contre les Myopathies16171
Ontario Brain Institute
Tel Aviv University

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