title: Polyglucosan neurotoxicity caused by glycogen branching enzyme deficiency can be reversed by inhibition of glycogen synthase.
abstract: Uncontrolled elongation of glycogen chains, not adequately balanced by their branching, leads to the formation of an insoluble, presumably neurotoxic, form of glycogen called polyglucosan. To test the suspected pathogenicity of polyglucosans in neurological glycogenoses, we have modeled the typical glycogenosis Adult Polyglucosan Body Disease (APBD) by suppressing glycogen branching enzyme 1 (GBE1, EC 2.4.1.18) expression using lentiviruses harboring short hairpin RNA (shRNA). GBE1 suppression in embryonic cortical neurons led to polyglucosan accumulation and associated apoptosis, which were reversible by rapamycin or starvation treatments. Further analysis revealed that rapamycin and starvation led to phosphorylation and inactivation of glycogen synthase (GS, EC 2.4.1.11), dephosphorylated and activated in the GBE1-suppressed neurons. These protective effects of rapamycin and starvation were reversed by overexpression of phosphorylation site mutant GS only if its glycogen binding site was intact. While rapamycin and starvation induce autophagy, autophagic maturation was not required for their corrective effects, which prevailed even if autophagic flux was inhibited by vinblastine. Furthermore, polyglucosans were not observed in any compartment along the autophagic pathway. Our data suggest that glycogen branching enzyme repression in glycogenoses can cause pathogenic polyglucosan buildup, which might be corrected by GS inhibition.
authors.affiliation: Department of Neurology, Hadassah-Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel.
authors.forename: Or
authors.initials: O
authors.lastname: Kakhlon
authors.forename: Hava
authors.initials: H
authors.lastname: Glickstein
authors.forename: Naomi
authors.initials: N
authors.lastname: Feinstein
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Otto
authors.initials: O
authors.lastname: Baba
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Terashima
authors.forename: Hasan Orhan
authors.initials: HO
authors.lastname: Akman
authors.forename: Salvatore
authors.initials: S
authors.lastname: Dimauro
authors.forename: Alexander
authors.initials: A
authors.lastname: Lossos
mesh_terms: D015061:1,4-alpha-Glucan Branching Enzyme / Q000187:drug effects* / Q000235:genetics; D000255:Adenosine Triphosphate / Q000378:metabolism; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005936:Glucans / Q000633:toxicity*; D006008:Glycogen Storage Disease / Q000378:metabolism; D006006:Glycogen Synthase / Q000037:antagonists & inhibitors*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008856:Microscopy, Fluorescence; D020258:Neurotoxicity Syndromes / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*; D010766:Phosphorylation; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D013217:Starvation / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D004791:Enzyme Inhibitors; D005936:Glucans; D034741:RNA, Small Interfering; D000255:Adenosine Triphosphate; C083094:polyglucosan; D006006:Glycogen Synthase; D015061:1,4-alpha-Glucan Branching Enzyme; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases
keywords: adult polyglucosan body disease; autophagy; glycogen branching enzyme; glycogen synthase; polyglucosan; polyglucosan bodies