Hyperphosphorylation of glucosyl c6 carbons and altered structure of glycogen in the neurodegenerative epilepsy lafora disease

Felix Nitschke, Peixiang Wang, Peter Schmieder, Jean Marie Girard, Donald E. Awrey, Tony Wang, Johan Israelian, Xiaochu Zhao, Julie Turnbull, Matthias Heydenreich, Erich Kleinpeter, Martin Steup, Berge A. Minassian

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Abstract

Laforin or malin deficiency causes Lafora disease, characterized by altered glycogen metabolism and teenage-onset neurodegeneration with intractable and invariably fatal epilepsy. Plant starches possess small amounts of metabolically essential monophosphate esters. Glycogen contains similar phosphate amounts, which are thought to originate from a glycogen synthase error side reaction and therefore lack any specific function. Glycogen is also believed to lack monophosphates at glucosyl carbon C6, an essential phosphorylation site in plant starch metabolism. We now show that glycogen phosphorylation is not due to a glycogen synthase side reaction, that C6 is a major glycogen phosphorylation site, and that C6 monophosphates predominate near centers of glycogen molecules and positively correlate with glycogen chain lengths. Laforin or malin deficiency causes C6 hyperphosphorylation, which results in malformed long-chained glycogen that accumulates in many tissues, causing neurodegeneration in brain. Our work advances the understanding of Lafora disease pathogenesis and suggests that glycogen phosphorylation has important metabolic function.

Original languageEnglish (US)
Pages (from-to)756-767
Number of pages12
JournalCell Metabolism
Volume17
Issue number5
DOIs
StatePublished - May 7 2013

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ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Nitschke, F., Wang, P., Schmieder, P., Girard, J. M., Awrey, D. E., Wang, T., Israelian, J., Zhao, X., Turnbull, J., Heydenreich, M., Kleinpeter, E., Steup, M., & Minassian, B. A. (2013). Hyperphosphorylation of glucosyl c6 carbons and altered structure of glycogen in the neurodegenerative epilepsy lafora disease. Cell Metabolism, 17(5), 756-767. https://doi.org/10.1016/j.cmet.2013.04.006