Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease

Felix Nitschke, Mitchell A. Sullivan, Peixiang Wang, Xiaochu Zhao, Erin E. Chown, Ami M. Perri, Lori Israelian, Lucia Juana-López, Paola Bovolenta, Santiago Rodríguez de Córdoba, Martin Steup, Berge A. Minassian

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Lafora disease (LD) is a fatal progressive epilepsy essentially caused by loss-of-function mutations in the glycogen phosphatase laforin or the ubiquitin E3 ligase malin. Glycogen in LD is hyperphosphorylated and poorly hydrosoluble. It precipitates and accumulates into neurotoxic Lafora bodies (LBs). The leading LD hypothesis that hyperphosphorylation causes the insolubility was recently challenged by the observation that phosphatase-inactive laforin rescues the laforin-deficient LD mouse model, apparently through correction of a general autophagy impairment. We were for the first time able to quantify brain glycogen phosphate. We also measured glycogen content and chain lengths, LBs, and autophagy markers in several laforin- or malin-deficient mouse lines expressing phosphatase-inactive laforin. We find that: (i) in laforin-deficient mice, phosphatase-inactive laforin corrects glycogen chain lengths, and not hyperphosphorylation, which leads to correction of glycogen amounts and prevention of LBs; (ii) in malin-deficient mice, phosphatase-inactive laforin confers no correction; (iii) general impairment of autophagy is not necessary in LD. We conclude that laforin's principle function is to control glycogen chain lengths, in a malin-dependent fashion, and that loss of this control underlies LD.

Original languageEnglish (US)
Pages (from-to)906-917
Number of pages12
JournalEMBO Molecular Medicine
Volume9
Issue number7
DOIs
StatePublished - Jul 2017

Keywords

  • Lafora disease
  • glycogen chain length
  • glycogen phosphorylation
  • laforin
  • malin

ASJC Scopus subject areas

  • Molecular Medicine

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    Nitschke, F., Sullivan, M. A., Wang, P., Zhao, X., Chown, E. E., Perri, A. M., Israelian, L., Juana-López, L., Bovolenta, P., Rodríguez de Córdoba, S., Steup, M., & Minassian, B. A. (2017). Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease. EMBO Molecular Medicine, 9(7), 906-917. https://doi.org/10.15252/emmm.201707608