Glycogen hyperphosphorylation underlies Lafora body formation

Julie Turnbull, Peixiang Wang, Jean Marie Girard, Alessandra Ruggieri, Tony J. Wang, Arman G. Draginov, Alexander P. Kameka, Nela Pencea, Xiaochu Zhao, Cameron A. Ackerley, Berge A. Minassian

Research output: Contribution to journalArticle

Abstract

Objective: Glycogen, the largest cytosolic macromolecule, acquires solubility, essential to its function, through extreme branching. Lafora bodies are aggregates of polyglucosan, a long, linear, poorly branched, and insoluble form of glycogen. Lafora bodies occupy vast numbers of neuronal dendrites and perikarya in Lafora disease in time-dependent fashion, leading to intractable and fatal progressive myoclonus epilepsy. Lafora disease is caused by deficiency of either the laforin glycogen phosphatase or the malin E3 ubiquitin ligase. The 2 leading hypotheses of Lafora body formation are: (1) increased glycogen synthase activity extends glycogen strands too rapidly to allow adequate branching, resulting in polyglucosans; and (2) increased glycogen phosphate leads to glycogen conformational change, unfolding, precipitation, and conversion to polyglucosan. Recently, it was shown that in the laforin phosphatase-deficient form of Lafora disease, there is no increase in glycogen synthase, but there is a dramatic increase in glycogen phosphate, with subsequent conversion of glycogen to polyglucosan. Here, we determine whether Lafora bodies in the malin ubiquitin ligase-deficient form of the disease are due to increased glycogen synthase or increased glycogen phosphate. Methods: We generated malin-deficient mice and tested the 2 hypotheses. Results: Malin-deficient mice precisely replicate the pathology of Lafora disease with Lafora body formation in skeletal muscle, liver, and brain, and in the latter in the pathognomonic perikaryal and dendritic locations. Glycogen synthase quantity and activity are unchanged. There is a highly significant increase in glycogen phosphate. Interpretation: We identify a single common modification, glycogen hyperphosphorylation, as the root cause of Lafora body pathogenesis. ANN NEUROL, 2010

Original languageEnglish
Pages (from-to)925-933
Number of pages9
JournalAnnals of Neurology
Volume68
Issue number6
DOIs
Publication statusPublished - Dec 2010

Fingerprint

Glycogen
Lafora Disease
Glycogen Synthase
Phosphates
Phosphoric Monoester Hydrolases
Progressive Myoclonic Epilepsy
Ubiquitin-Protein Ligases
Ligases
Dendrites
Ubiquitin
Solubility
Skeletal Muscle
Pathology
polyglucosan
Liver

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Turnbull, J., Wang, P., Girard, J. M., Ruggieri, A., Wang, T. J., Draginov, A. G., ... Minassian, B. A. (2010). Glycogen hyperphosphorylation underlies Lafora body formation. Annals of Neurology, 68(6), 925-933. https://doi.org/10.1002/ana.22156

Glycogen hyperphosphorylation underlies Lafora body formation. / Turnbull, Julie; Wang, Peixiang; Girard, Jean Marie; Ruggieri, Alessandra; Wang, Tony J.; Draginov, Arman G.; Kameka, Alexander P.; Pencea, Nela; Zhao, Xiaochu; Ackerley, Cameron A.; Minassian, Berge A.

In: Annals of Neurology, Vol. 68, No. 6, 12.2010, p. 925-933.

Research output: Contribution to journalArticle

Turnbull, J, Wang, P, Girard, JM, Ruggieri, A, Wang, TJ, Draginov, AG, Kameka, AP, Pencea, N, Zhao, X, Ackerley, CA & Minassian, BA 2010, 'Glycogen hyperphosphorylation underlies Lafora body formation', Annals of Neurology, vol. 68, no. 6, pp. 925-933. https://doi.org/10.1002/ana.22156
Turnbull J, Wang P, Girard JM, Ruggieri A, Wang TJ, Draginov AG et al. Glycogen hyperphosphorylation underlies Lafora body formation. Annals of Neurology. 2010 Dec;68(6):925-933. https://doi.org/10.1002/ana.22156
Turnbull, Julie ; Wang, Peixiang ; Girard, Jean Marie ; Ruggieri, Alessandra ; Wang, Tony J. ; Draginov, Arman G. ; Kameka, Alexander P. ; Pencea, Nela ; Zhao, Xiaochu ; Ackerley, Cameron A. ; Minassian, Berge A. / Glycogen hyperphosphorylation underlies Lafora body formation. In: Annals of Neurology. 2010 ; Vol. 68, No. 6. pp. 925-933.
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AB - Objective: Glycogen, the largest cytosolic macromolecule, acquires solubility, essential to its function, through extreme branching. Lafora bodies are aggregates of polyglucosan, a long, linear, poorly branched, and insoluble form of glycogen. Lafora bodies occupy vast numbers of neuronal dendrites and perikarya in Lafora disease in time-dependent fashion, leading to intractable and fatal progressive myoclonus epilepsy. Lafora disease is caused by deficiency of either the laforin glycogen phosphatase or the malin E3 ubiquitin ligase. The 2 leading hypotheses of Lafora body formation are: (1) increased glycogen synthase activity extends glycogen strands too rapidly to allow adequate branching, resulting in polyglucosans; and (2) increased glycogen phosphate leads to glycogen conformational change, unfolding, precipitation, and conversion to polyglucosan. Recently, it was shown that in the laforin phosphatase-deficient form of Lafora disease, there is no increase in glycogen synthase, but there is a dramatic increase in glycogen phosphate, with subsequent conversion of glycogen to polyglucosan. Here, we determine whether Lafora bodies in the malin ubiquitin ligase-deficient form of the disease are due to increased glycogen synthase or increased glycogen phosphate. Methods: We generated malin-deficient mice and tested the 2 hypotheses. Results: Malin-deficient mice precisely replicate the pathology of Lafora disease with Lafora body formation in skeletal muscle, liver, and brain, and in the latter in the pathognomonic perikaryal and dendritic locations. Glycogen synthase quantity and activity are unchanged. There is a highly significant increase in glycogen phosphate. Interpretation: We identify a single common modification, glycogen hyperphosphorylation, as the root cause of Lafora body pathogenesis. ANN NEUROL, 2010

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