Journal Article

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 and Berge A. Minassian

in Human Molecular Genetics

Volume 13, issue 11, pages 1117-1129
Published in print June 2004 | ISSN: 0964-6906
Published online April 2004 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddh130
Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy

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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.

Journal Article.  6473 words.  Illustrated.

Subjects: Genetics and Genomics

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