Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy

Elayne M. Chan, Cameron A. Ackerley, Hannes Lohi, Leonarda Ianzano, Miguel A. Cortez, Patrick Shannon, Stephen W. Scherer, Berge A. Minassian

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

Lafora disease (LD) is a fatal and the most common form of adolescent-onset progressive epilepsy. Fulminant endoplasmic reticulum (ER)-associated depositions of starch-like long-stranded, poorly branched glycogen molecules [known as polyglucosans, which accumulate to form Lafora bodies (LBs)] are seen in neuronal perikarya and dendrites, liver, skeletal muscle and heart. The disease is caused by loss of function of the laforin dual-specificity phosphatase or the malin E3 ubiquitin ligase. Towards understanding the pathogenesis of polyglucosans in LD, we generated a transgenic mouse overexpressing inactivated laforin to trap normal laforin's unknown substrate. The trap was successful and LBs formed in liver, muscle, neuronal perikarya and dendrites. Using immunogold electron microscopy, we show that laforin is found in close proximity to the ER surrounding the polyglucosan accumulations. In neurons, it compartmentalizes to perikaryon and dendrites and not to axons. Importantly, it binds polyglucosans, establishing for the first time a direct association between the disease-defining storage product and disease protein. It preferentially binds polyglucosans over glycogen in vivo and starch over glycogen in vitro, suggesting that laforin's role begins after the appearance of polyglucosans and that the laforin pathway is involved in monitoring for and then preventing the formation of polyglucosans. In addition, we show that the laforin interacting protein, EPM2AIP1, also localizes on the polyglucosan masses, and we confirm laforin's intense binding to LBs in human LD biopsy material.

Original languageEnglish (US)
Pages (from-to)1117-1129
Number of pages13
JournalHuman Molecular Genetics
Volume13
Issue number11
DOIs
StatePublished - Jun 1 2004

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Progressive Myoclonic Epilepsy
Starch
Lafora Disease
Dendrites
Glycogen
Endoplasmic Reticulum
Dual-Specificity Phosphatases
Ubiquitin-Protein Ligases
polyglucosan
Liver
Human Body
Transgenic Mice
Axons
Epilepsy
Electron Microscopy
Skeletal Muscle
Proteins
Biopsy
Neurons
Muscles

ASJC Scopus subject areas

  • Genetics

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Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy. / Chan, Elayne M.; Ackerley, Cameron A.; Lohi, Hannes; Ianzano, Leonarda; Cortez, Miguel A.; Shannon, Patrick; Scherer, Stephen W.; Minassian, Berge A.

In: Human Molecular Genetics, Vol. 13, No. 11, 01.06.2004, p. 1117-1129.

Research output: Contribution to journalArticle

Chan, Elayne M. ; Ackerley, Cameron A. ; Lohi, Hannes ; Ianzano, Leonarda ; Cortez, Miguel A. ; Shannon, Patrick ; Scherer, Stephen W. ; Minassian, Berge A. / Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy. In: Human Molecular Genetics. 2004 ; Vol. 13, No. 11. pp. 1117-1129.
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AU - Chan, Elayne M.

AU - Ackerley, Cameron A.

AU - Lohi, Hannes

AU - Ianzano, Leonarda

AU - Cortez, Miguel A.

AU - Shannon, Patrick

AU - Scherer, Stephen W.

AU - Minassian, Berge A.

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N2 - Lafora disease (LD) is a fatal and the most common form of adolescent-onset progressive epilepsy. Fulminant endoplasmic reticulum (ER)-associated depositions of starch-like long-stranded, poorly branched glycogen molecules [known as polyglucosans, which accumulate to form Lafora bodies (LBs)] are seen in neuronal perikarya and dendrites, liver, skeletal muscle and heart. The disease is caused by loss of function of the laforin dual-specificity phosphatase or the malin E3 ubiquitin ligase. Towards understanding the pathogenesis of polyglucosans in LD, we generated a transgenic mouse overexpressing inactivated laforin to trap normal laforin's unknown substrate. The trap was successful and LBs formed in liver, muscle, neuronal perikarya and dendrites. Using immunogold electron microscopy, we show that laforin is found in close proximity to the ER surrounding the polyglucosan accumulations. In neurons, it compartmentalizes to perikaryon and dendrites and not to axons. Importantly, it binds polyglucosans, establishing for the first time a direct association between the disease-defining storage product and disease protein. It preferentially binds polyglucosans over glycogen in vivo and starch over glycogen in vitro, suggesting that laforin's role begins after the appearance of polyglucosans and that the laforin pathway is involved in monitoring for and then preventing the formation of polyglucosans. In addition, we show that the laforin interacting protein, EPM2AIP1, also localizes on the polyglucosan masses, and we confirm laforin's intense binding to LBs in human LD biopsy material.

AB - Lafora disease (LD) is a fatal and the most common form of adolescent-onset progressive epilepsy. Fulminant endoplasmic reticulum (ER)-associated depositions of starch-like long-stranded, poorly branched glycogen molecules [known as polyglucosans, which accumulate to form Lafora bodies (LBs)] are seen in neuronal perikarya and dendrites, liver, skeletal muscle and heart. The disease is caused by loss of function of the laforin dual-specificity phosphatase or the malin E3 ubiquitin ligase. Towards understanding the pathogenesis of polyglucosans in LD, we generated a transgenic mouse overexpressing inactivated laforin to trap normal laforin's unknown substrate. The trap was successful and LBs formed in liver, muscle, neuronal perikarya and dendrites. Using immunogold electron microscopy, we show that laforin is found in close proximity to the ER surrounding the polyglucosan accumulations. In neurons, it compartmentalizes to perikaryon and dendrites and not to axons. Importantly, it binds polyglucosans, establishing for the first time a direct association between the disease-defining storage product and disease protein. It preferentially binds polyglucosans over glycogen in vivo and starch over glycogen in vitro, suggesting that laforin's role begins after the appearance of polyglucosans and that the laforin pathway is involved in monitoring for and then preventing the formation of polyglucosans. In addition, we show that the laforin interacting protein, EPM2AIP1, also localizes on the polyglucosan masses, and we confirm laforin's intense binding to LBs in human LD biopsy material.

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