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• W157717640 abstract "OBJECTIVE: The purpose of our work is to find ways to reverse the adverse effects of Polyglucosan bodies (PB) in APBD and other PB-associated disorders. BACKGROUND: Polyglucosans are poorly branched polysaccharides formed by excessive glycogen elongation at the expense of its branching. Polyglucosans tend to aggregate into presumably pathogenic, non membrane-bound, large (> 1µm) fibrous structures called PB. PB are found in neurometabolic disorders such as APBD and Lafora Disease (LD), respectively characterized by deficient glycogen branching enzyme (GBE) and excessive glycogen synthase (GS) activities. These disorders are currently incurable. DESIGN/METHODS: Neuronal and mouse models of APBD were generated by suppressing GBE expression using GBE short-helical-RNA-lentivirus transduction and GBEY329S knockin, respectively. GBE, the autophagy marker LC3 and PB levels were assessed by immunoblotting and indirect immunofluorescence. GBE and GS activities were assessed by 14C-glucose incorporation into glycogen. Apoptosis and autophagy were assessed by flow cytometry and transmission electron microscopy, respectively. Small molecules, computationally designed peptides, and triple-helix-forming-oligos (TFO) targeting GS are tested by high throughput screening (HTS) for their ability to reduce PB accumulation, using Periodic Acid Schiff (PAS) staining. APBD-patient-derived skin fibroblasts and brain cultures from APBD mouse models are used for the HTS. RESULTS: GBE-suppressed neurons were apoptotic and showed PB accumulation, similar to APBD patient-derived cells. Inducers of autophagy cleared PB and reversed their damage, but did so via inhibition of GS activity, rather than PB engulfment in autophagosomes. CONCLUSIONS: Our result that autophagy inducers clear PB and reverse their damage by inhibiting GS suggests a strategy for treating APBD and LD via lowering the ratio between glycogen synthesis and branching in order to reduce the levels of neurotoxic PB. This strategy is currently implemented in HTS-based search for GS inhibitors (small molecules, TFO, peptides), GBE stabilizers (small molecules, peptides), or drugs promoting PB degradation. Supported by: APBD Research Foundation; Association Francaise contre les Myopathies (AFM) - grant approved for funding. Disclosure: Dr. Kakhlon has nothing to disclose. Dr. Glickstein has nothing to disclose. Dr. Feinstein has nothing to disclose. Dr. Akman has nothing to disclose. Dr. DiMauro has received personal compensation in an editorial capacity for MedLink Neurology. Dr. Minassian has nothing to disclose. Dr. Michaeli has nothing to disclose. Dr. Rayan has nothing to disclose. Dr. Grossman has nothing to disclose. Dr. Solmesky has nothing to disclose. Dr. Weil has nothing to disclose. Dr. Kozakov has nothing to disclose. Dr. Lossos has nothing to disclose." @default.
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• W157717640 date "2013-02-12" @default.
• W157717640 modified "2023-10-13" @default.
• W157717640 title "Searching for Efficient Therapeutic Avenues To Treat Adult Polyglucosan Body Disease (APBD) and Lafora Disease (LD) Using a High-Throughput Screening Platform (P03.053)" @default.
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