Laforin is a glycogen phosphatase, deficiency of which leads to elevated phosphorylation of glycogen in vivo

Vincent S. Tagliabracci, Julie Turnbull, Wei Wang, Jean Marie Girard, Xiaochu Zhao, Alexander Skurat, Antonio V. Delgado-Escueta, Berge A. Minassian, Anna De Paoli-Roach, Peter Roach

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

Lafora disease is a progressive myoclonus epilepsy with onset typically in the second decade of life and death within 10 years. Lafora bodies, deposits of abnormally branched, insoluble glycogen-like polymers, form in neurons, muscle, liver, and other tissues. Approximately half of the cases of Lafora disease result from mutations in the EPM2A gene, which encodes laforin, a member of the dual-specificity protein phosphatase family that additionally contains a glycogen binding domain. The molecular basis for the formation of Lafora bodies is completely unknown. Glycogen, a branched polymer of glucose, contains a small amount of covalently linked phosphate whose origin and function are obscure. We report here that recombinant laforin is able to release this phosphate in vitro, in a time-dependent reaction with an apparent Km for glycogen of 4.5 mg/ml. Mutations of laforin that disable the glycogen binding domain also eliminate its ability to dephosphorylate glycogen. We have also analyzed glycogen from a mouse model of Lafora disease, Epm2a-/- mice, which develop Lafora bodies in several tissues. Glycogen isolated from these mice had a 40% increase in the covalent phosphate content in liver and a 4-fold elevation in muscle. We propose that excessive phosphorylation of glycogen leads to aberrant branching and Lafora body formation. This study provides a molecular link between an observed biochemical property of laforin and the phenotype of a mouse model of Lafora disease. The results also have important implications for glycogen metabolism generally.

Original languageEnglish
Pages (from-to)19262-19266
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number49
DOIs
StatePublished - Dec 4 2007

Fingerprint

Glycogen
Phosphoric Monoester Hydrolases
Phosphorylation
Lafora Disease
Phosphates
Dual-Specificity Phosphatases
Progressive Myoclonic Epilepsy
Muscles
Mutation
Glucans
Phosphoprotein Phosphatases
Liver
Polymers
Phenotype
Neurons

Keywords

  • Epm2a
  • Lafora bodies
  • Phosphate
  • Polyglucosan

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Laforin is a glycogen phosphatase, deficiency of which leads to elevated phosphorylation of glycogen in vivo. / Tagliabracci, Vincent S.; Turnbull, Julie; Wang, Wei; Girard, Jean Marie; Zhao, Xiaochu; Skurat, Alexander; Delgado-Escueta, Antonio V.; Minassian, Berge A.; De Paoli-Roach, Anna; Roach, Peter.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 49, 04.12.2007, p. 19262-19266.

Research output: Contribution to journalArticle

Tagliabracci, Vincent S. ; Turnbull, Julie ; Wang, Wei ; Girard, Jean Marie ; Zhao, Xiaochu ; Skurat, Alexander ; Delgado-Escueta, Antonio V. ; Minassian, Berge A. ; De Paoli-Roach, Anna ; Roach, Peter. / Laforin is a glycogen phosphatase, deficiency of which leads to elevated phosphorylation of glycogen in vivo. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 49. pp. 19262-19266.
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AU - Zhao, Xiaochu

AU - Skurat, Alexander

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