Human Molecular Genetics Advance Access originally published online on April 21, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 11 1117-1129
DOI: 10.1093/hmg/ddh130
Human Molecular Genetics, Vol. 13, No. 11 © Oxford University Press 2004; all rights reserved
Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy
1Program in Genetics and Genomic Biology, Research Institute, The Hospital for Sick Children and Department of Molecular and Medical Genetics, the University of Toronto, Toronto, M5G 1X8, Canada, 2Division of Pathology, Department of Pediatric Laboratory Medicine and 3Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, Toronto, M5G 1X8, Canada and 4Department of Neuropathology, Toronto Western Hospital and the University of Toronto, Toronto, M5T 2S8, Canada
Received January 23, 2004; Accepted April 2, 2004
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.
* To whom correspondence should be addressed. Tel: +1 4168136291; Fax: +1 4168136334; Email: bminass{at}sickkids.ca
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