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Polyglucosan neurotoxicity caused by glycogen branching enzyme deficiency can be reversed by inhibition of glycogen synthase
- Source :
- Journal of neurochemistry. 127(1)
- Publication Year :
- 2013
-
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. 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.
- Subjects :
- Primary Cell Culture
Apoptosis
Real-Time Polymerase Chain Reaction
Biochemistry
Glycogen debranching enzyme
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Glycogen phosphorylase
Adenosine Triphosphate
Transduction, Genetic
1,4-alpha-Glucan Branching Enzyme
Glycogen branching enzyme
Animals
Humans
Lymphocytes
Enzyme Inhibitors
Phosphorylation
RNA, Small Interfering
Glycogen synthase
GSK3B
Glucans
Aged
Cerebral Cortex
Glycogen binding
biology
Glycogen
TOR Serine-Threonine Kinases
Fibroblasts
Glycogen Storage Disease
Rats
Glycogen Branching Enzyme Deficiency
Glycogen Synthase
chemistry
Microscopy, Fluorescence
Starvation
biology.protein
Female
Neurotoxicity Syndromes
Subjects
Details
- ISSN :
- 14714159
- Volume :
- 127
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of neurochemistry
- Accession number :
- edsair.doi.dedup.....b38ad765c6af5df82a667c42ac20c695