Increased laforin and laforin binding to glycogen underlie lafora body formation in malin-deficient lafora disease

Erica Tiberia, Julie Turnbull, Tony Wang, Alessandra Ruggieri, Xiao Chu Zhao, Nela Pencea, Johan Israelian, Yin Wang, Cameron A. Ackerley, Peixiang Wang, Yan Liu, Berge A. Minassian

Research output: Contribution to journalArticle

Abstract

The solubility of glycogen, essential to its metabolism, is a property of its shape, a sphere generated through extensive branching during synthesis. Lafora disease (LD) is a severe teenage-onset neurodegenerative epilepsy and results from multiorgan accumulations, termed Lafora bodies (LB), of abnormally structured aggregation-prone and digestion-resistant glycogen. LD is caused by loss-of-function mutations in the EPM2A or EPM2B gene, encoding the interacting laforin phosphatase and malin E3 ubiquitin ligase enzymes, respectively. The substrate and function of malin are unknown; an early counterintuitive observation in cell culture experiments that it targets laforin to proteasomal degradation was not pursued until now. The substrate and function of laforin have recently been elucidated. Laforin dephosphorylates glycogen during synthesis, without which phosphate ions interfere with and distort glycogen construction, leading to LB. We hypothesized that laforin in excess or not removed following its action on glycogen also interferes with glycogen formation. We show in malin-deficient mice that the absence of malin results in massively increased laforin preceding the appearance of LB and that laforin gradually accumulates in glycogen, which corresponds to progressive LB generation. We show that increasing the amounts of laforin in cell culture causes LB formation and that this occurs only with glycogen binding-competent laforin. In summary, malin deficiency causes increased laforin, increased laforin binding to glycogen, and LB formation. Furthermore, increased levels of laforin, when it can bind glycogen, causes LB. We conclude that malin functions to regulate laforin and that malin deficiency at least in part causes LB and LD through increased laforin binding to glycogen.

Original languageEnglish
Pages (from-to)25650-25659
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number30
DOIs
Publication statusPublished - Jul 20 2012

Fingerprint

Lafora Disease
Glycogen
Cell culture
Cell Culture Techniques
Gene encoding
Ubiquitin-Protein Ligases
Substrates
Phosphoric Monoester Hydrolases
Metabolism
Solubility

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Tiberia, E., Turnbull, J., Wang, T., Ruggieri, A., Zhao, X. C., Pencea, N., ... Minassian, B. A. (2012). Increased laforin and laforin binding to glycogen underlie lafora body formation in malin-deficient lafora disease. Journal of Biological Chemistry, 287(30), 25650-25659. https://doi.org/10.1074/jbc.M111.331611

Increased laforin and laforin binding to glycogen underlie lafora body formation in malin-deficient lafora disease. / Tiberia, Erica; Turnbull, Julie; Wang, Tony; Ruggieri, Alessandra; Zhao, Xiao Chu; Pencea, Nela; Israelian, Johan; Wang, Yin; Ackerley, Cameron A.; Wang, Peixiang; Liu, Yan; Minassian, Berge A.

In: Journal of Biological Chemistry, Vol. 287, No. 30, 20.07.2012, p. 25650-25659.

Research output: Contribution to journalArticle

Tiberia, E, Turnbull, J, Wang, T, Ruggieri, A, Zhao, XC, Pencea, N, Israelian, J, Wang, Y, Ackerley, CA, Wang, P, Liu, Y & Minassian, BA 2012, 'Increased laforin and laforin binding to glycogen underlie lafora body formation in malin-deficient lafora disease', Journal of Biological Chemistry, vol. 287, no. 30, pp. 25650-25659. https://doi.org/10.1074/jbc.M111.331611
Tiberia, Erica ; Turnbull, Julie ; Wang, Tony ; Ruggieri, Alessandra ; Zhao, Xiao Chu ; Pencea, Nela ; Israelian, Johan ; Wang, Yin ; Ackerley, Cameron A. ; Wang, Peixiang ; Liu, Yan ; Minassian, Berge A. / Increased laforin and laforin binding to glycogen underlie lafora body formation in malin-deficient lafora disease. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 30. pp. 25650-25659.
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AU - Tiberia, Erica

AU - Turnbull, Julie

AU - Wang, Tony

AU - Ruggieri, Alessandra

AU - Zhao, Xiao Chu

AU - Pencea, Nela

AU - Israelian, Johan

AU - Wang, Yin

AU - Ackerley, Cameron A.

AU - Wang, Peixiang

AU - Liu, Yan

AU - Minassian, Berge A.

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N2 - The solubility of glycogen, essential to its metabolism, is a property of its shape, a sphere generated through extensive branching during synthesis. Lafora disease (LD) is a severe teenage-onset neurodegenerative epilepsy and results from multiorgan accumulations, termed Lafora bodies (LB), of abnormally structured aggregation-prone and digestion-resistant glycogen. LD is caused by loss-of-function mutations in the EPM2A or EPM2B gene, encoding the interacting laforin phosphatase and malin E3 ubiquitin ligase enzymes, respectively. The substrate and function of malin are unknown; an early counterintuitive observation in cell culture experiments that it targets laforin to proteasomal degradation was not pursued until now. The substrate and function of laforin have recently been elucidated. Laforin dephosphorylates glycogen during synthesis, without which phosphate ions interfere with and distort glycogen construction, leading to LB. We hypothesized that laforin in excess or not removed following its action on glycogen also interferes with glycogen formation. We show in malin-deficient mice that the absence of malin results in massively increased laforin preceding the appearance of LB and that laforin gradually accumulates in glycogen, which corresponds to progressive LB generation. We show that increasing the amounts of laforin in cell culture causes LB formation and that this occurs only with glycogen binding-competent laforin. In summary, malin deficiency causes increased laforin, increased laforin binding to glycogen, and LB formation. Furthermore, increased levels of laforin, when it can bind glycogen, causes LB. We conclude that malin functions to regulate laforin and that malin deficiency at least in part causes LB and LD through increased laforin binding to glycogen.

AB - The solubility of glycogen, essential to its metabolism, is a property of its shape, a sphere generated through extensive branching during synthesis. Lafora disease (LD) is a severe teenage-onset neurodegenerative epilepsy and results from multiorgan accumulations, termed Lafora bodies (LB), of abnormally structured aggregation-prone and digestion-resistant glycogen. LD is caused by loss-of-function mutations in the EPM2A or EPM2B gene, encoding the interacting laforin phosphatase and malin E3 ubiquitin ligase enzymes, respectively. The substrate and function of malin are unknown; an early counterintuitive observation in cell culture experiments that it targets laforin to proteasomal degradation was not pursued until now. The substrate and function of laforin have recently been elucidated. Laforin dephosphorylates glycogen during synthesis, without which phosphate ions interfere with and distort glycogen construction, leading to LB. We hypothesized that laforin in excess or not removed following its action on glycogen also interferes with glycogen formation. We show in malin-deficient mice that the absence of malin results in massively increased laforin preceding the appearance of LB and that laforin gradually accumulates in glycogen, which corresponds to progressive LB generation. We show that increasing the amounts of laforin in cell culture causes LB formation and that this occurs only with glycogen binding-competent laforin. In summary, malin deficiency causes increased laforin, increased laforin binding to glycogen, and LB formation. Furthermore, increased levels of laforin, when it can bind glycogen, causes LB. We conclude that malin functions to regulate laforin and that malin deficiency at least in part causes LB and LD through increased laforin binding to glycogen.

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