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A novel image-based high-throughput screening assay discovers therapeutic candidates for adult polyglucosan body disease
- Source :
- Biochemical Journal. 474:3403-3420
- Publication Year :
- 2017
- Publisher :
- Portland Press Ltd., 2017.
-
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.
- Subjects :
- Adult
Male
0301 basic medicine
High-throughput screening
Cell
Phosphatase
Drug Evaluation, Preclinical
Biology
Biochemistry
Article
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
medicine
Humans
Glycogen synthase
Molecular Biology
Glycogen
Cell Biology
Adult polyglucosan body disease
Fibroblasts
Glycogen Storage Disease
Glycogen Synthase
030104 developmental biology
medicine.anatomical_structure
chemistry
biology.protein
Female
Nervous System Diseases
030217 neurology & neurosurgery
Image based
Intracellular
Subjects
Details
- ISSN :
- 14708728 and 02646021
- Volume :
- 474
- Database :
- OpenAIRE
- Journal :
- Biochemical Journal
- Accession number :
- edsair.doi.dedup.....1086baab83b2e045a92bb09570398a7b