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To test the suspected pathogenicity of polyglucosans in neurological glycogenoses, we have modeled the typical glycogenosis Adult Polyglucosan Body Disease (<jats:styled-content style=\"fixed-case\">APBD<\/jats:styled-content>) by suppressing glycogen branching enzyme 1 (<jats:styled-content style=\"fixed-case\">GBE<\/jats:styled-content>1, <jats:styled-content style=\"fixed-case\">EC<\/jats:styled-content> 2.4.1.18) expression using lentiviruses harboring short hairpin <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> (sh<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>). <jats:styled-content style=\"fixed-case\">GBE<\/jats:styled-content>1 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 (<jats:styled-content style=\"fixed-case\">GS<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> EC<\/jats:styled-content> 2.4.1.11), dephosphorylated and activated in the <jats:styled-content style=\"fixed-case\">GBE<\/jats:styled-content>1\u2010suppressed neurons. These protective effects of rapamycin and starvation were reversed by overexpression of phosphorylation site mutant <jats:styled-content style=\"fixed-case\">GS<\/jats:styled-content> 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 <jats:styled-content style=\"fixed-case\">GS<\/jats:styled-content> inhibition.<\/jats:p><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc12277-fig-0009-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><jats:p>Knockdown of glycogen branching enzyme in neurons led to accumulation of an insoluble form of glycogen called polyglucosan, to apoptosis and to activation of glycogen synthase. These effects were reversed by glycogen synthase inhibition through starvation and rapamycin treatments, suggesting a potential therapeutic value of glycogen synthase inhibition for treating glycogen storage disorders.<\/jats:p>","DOI":"10.1111\/jnc.12277","type":"journal-article","created":{"date-parts":[[2013,4,23]],"date-time":"2013-04-23T09:28:24Z","timestamp":1366709304000},"page":"101-113","source":"Crossref","is-referenced-by-count":27,"title":["Polyglucosan neurotoxicity caused by glycogen branching enzyme deficiency can be reversed by inhibition of glycogen synthase"],"prefix":"10.1111","volume":"127","author":[{"given":"Or","family":"Kakhlon","sequence":"first","affiliation":[{"name":"Department of Neurology Hadassah\u2010Hebrew University Medical Center Ein Kerem Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hava","family":"Glickstein","sequence":"additional","affiliation":[{"name":"Electron Microscope Unit Interdepartmental Core Facility Faculty of Medicine The Hebrew University of Jerusalem Ein Kerem Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naomi","family":"Feinstein","sequence":"additional","affiliation":[{"name":"Bio\u2010imaging Unit The Alexander Silverman Institute of Life Sciences The Hebrew University of Jerusalem Edmund Safra Campus Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Cancer and Immunology Research Children's National Medical Center Washington District of Columbia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Otto","family":"Baba","sequence":"additional","affiliation":[{"name":"Section of Biology Department of Oral Function &amp; Molecular Biology, School of Dentistry, Ohu University Fukushima Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuo","family":"Terashima","sequence":"additional","affiliation":[{"name":"Maxillofacial Anatomy Tokyo Medical and Dental University Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hasan Orhan","family":"Akman","sequence":"additional","affiliation":[{"name":"Department of Neurology Columbia University Medical Center New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salvatore","family":"DiMauro","sequence":"additional","affiliation":[{"name":"Department of Neurology Columbia University Medical Center New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Lossos","sequence":"additional","affiliation":[{"name":"Department of Neurology Hadassah\u2010Hebrew University Medical Center Ein Kerem Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,5,9]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq190"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr371"},{"key":"e_1_2_7_4_1","first-page":"83","article-title":"Lafora disease, seizures and sugars","volume":"26","author":"Andrade D. 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