Skeletal Muscle Glycogen Chain Length Correlates with Insolubility in Mouse Models of Polyglucosan-Associated Neurodegenerative Diseases

Lafora disease (LD) and adult polyglucosan body disease (APBD) are glycogen storage diseases characterized by a pathogenic buildup of insoluble glycogen. Mechanisms causing glycogen insolubility are poorly understood. Here, in two mouse models of LD (Epm2a−/− and Epm2b−/−) and one of APBD (Gbe1ys/ys...

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Published in:	Cell reports (Cambridge) Vol. 27; no. 5; pp. 1334 - 1344.e6
Main Authors:	Sullivan, Mitchell A., Nitschke, Silvia, Skwara, Evan P., Wang, Peixiang, Zhao, Xiaochu, Pan, Xiao S., Chown, Erin E., Wang, Travis, Perri, Ami M., Lee, Jennifer P.Y., Vilaplana, Francisco, Minassian, Berge A., Nitschke, Felix
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 30-04-2019 Elsevier
Subjects:	Animals APBD Female Glycogen - chemistry Glycogen - metabolism glycogen branching enzyme glycogen chain length distribution Glycogen Debranching Enzyme System - genetics glycogen storage disease Glycogen Storage Disease - genetics Glycogen Storage Disease - metabolism glycogen synthase HEK293 Cells Humans Lafora disease Lafora Disease - genetics Lafora Disease - metabolism laforin Male malin Membrane Glycoproteins - genetics Mice Mice, Inbred C57BL Muscle, Skeletal - metabolism Muscle, Skeletal - pathology Nervous System Diseases - genetics Nervous System Diseases - metabolism Phosphorylation polyglucosan bodies Solubility malin laforin glycogen chain length distribution glycogen storage disease glycogen branching enzyme glycogen synthase polyglucosan bodies phosphorylation Lafora disease APBD
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Summary:	Lafora disease (LD) and adult polyglucosan body disease (APBD) are glycogen storage diseases characterized by a pathogenic buildup of insoluble glycogen. Mechanisms causing glycogen insolubility are poorly understood. Here, in two mouse models of LD (Epm2a−/− and Epm2b−/−) and one of APBD (Gbe1ys/ys), the separation of soluble and insoluble muscle glycogen is described, enabling separate analysis of each fraction. Total glycogen is increased in LD and APBD mice, which, together with abnormal chain length and molecule size distributions, is largely if not fully attributed to insoluble glycogen. Soluble glycogen consists of molecules with distinct chain length distributions and differential corresponding solubility, providing a mechanistic link between soluble and insoluble glycogen in vivo. Phosphorylation states differ across glycogen fractions and mouse models, demonstrating that hyperphosphorylation is not a basic feature of insoluble glycogen. Lastly, model-specific variances in protein and activity levels of key glycogen synthesis enzymes suggest uninvestigated regulatory mechanisms. [Display omitted] •Soluble glycogen content and structure: WT-like in Epm2a−/−, Epm2b−/−, Gbe1ys/ys mice•Glycogen hyperphosphorylation is not a general feature of insoluble glycogen•Abnormal chain length and molecule size distributions are limited to insoluble glycogen•Wild-type glycogen molecules vary in average chain length and precipitation propensity EPM2A, EPM2B, or GBE1 deficiency causes insoluble glycogen accumulation and neurodegenerative diseases. Sullivan et al. show that these defects do not impair the construction of WT-like soluble glycogen. Demonstrating varying chain length distributions and correlating precipitation propensity among WT-glycogen molecules, a mechanistic explanation emerges for the structural characteristics of insoluble glycogen.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 M.A.S., S.N., B.A.M., and F.N. designed the study. M.A.S., S.N., and F.N. carried out experiments, analyzed and interpreted the data, and wrote the paper. E.P.S., P.W., X.Z., X.S.P., T.W., A.M.P., and J.P.Y.L. helped carry out experiments and analyze and interpret data. F.V. carried out experiments and, with E.E.C. and B.A.M., helped analyze and interpret data and revise the paper. AUTHOR CONTRIBUTIONS
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2019.04.017