Human Molecular Genetics Advance Access published online on April 21, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh130
© 2004 by Oxford University Press
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1 Program in Genetics and Genomic Biology, Research Institute, The Hospital for Sick Children and Department of Molecular and Medical Genetics, the University of Toronto, M5G 1X8, Canada
* To whom correspondence should be addressed. E-mail: bminass{at}sickkids.ca.
Lafora disease 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) 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 Lafora disease, we generated a transgenic mouse overexpressing inactivated laforin to trap normal laforin's unknown substrate. The trap was successful and Lafora bodies 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 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 additional experiments we show that the laforin interacting protein, EPM2AIP1, also localizes on the polyglucosan masses, and we confirm laforin's intense binding to Lafora bodies in human Lafora disease biopsy material.
Article
Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy
2 Division of Pathology, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, M5G 1X8, Canada
3 Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, Toronto, M5G 1X8, Canada
4 Department of Neuropathology, Toronto Western Hospital and the University of Toronto, M5T 2S8, Canada
5 Program in Genetics and Genomic Biology, Research Institute, The Hospital for Sick Children and Department of Molecular and Medical Genetics, the University of Toronto, M5G 1X8, Canada; Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, and the University of Toronto, M5G 1X8, Canada
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