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Int. J. Mol. Sci. 2017, 18(8), 1743; doi:10.3390/ijms18081743

Pathogenesis of Lafora Disease: Transition of Soluble Glycogen to Insoluble Polyglucosan

1
Program in Genetics and Genome Biology, The Hospital for Sick Children Research Institute, 686 Bay Street, Toronto, ON M5G 0A4, Canada
2
Glycation and Diabetes, Mater Research Institute, Translational Research Institute, The University of Queensland, 37 Kent St., Woolloongabba, Brisbane 4102, Australia
3
The Impact Centre of the University of Toronto, 60 St. George Street, Toronto, ON M5S 1A7, Canada
4
Faculty of Mathematics and Science, University of Potsdam, 14476 Potsdam-Golm, Germany
5
Division of Neurology, Department of Pediatrics, University of Texas Southwestern, 5323 Harry Hines Blvd., Dallas, TX 75390-9063, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Wolfram S. Kunz
Received: 17 July 2017 / Revised: 4 August 2017 / Accepted: 6 August 2017 / Published: 11 August 2017
View Full-Text   |   Download PDF [2829 KB, uploaded 11 August 2017]   |  

Abstract

Lafora disease (LD, OMIM #254780) is a rare, recessively inherited neurodegenerative disease with adolescent onset, resulting in progressive myoclonus epilepsy which is fatal usually within ten years of symptom onset. The disease is caused by loss-of-function mutations in either of the two genes EPM2A (laforin) or EPM2B (malin). It characteristically involves the accumulation of insoluble glycogen-derived particles, named Lafora bodies (LBs), which are considered neurotoxic and causative of the disease. The pathogenesis of LD is therefore centred on the question of how insoluble LBs emerge from soluble glycogen. Recent data clearly show that an abnormal glycogen chain length distribution, but neither hyperphosphorylation nor impairment of general autophagy, strictly correlates with glycogen accumulation and the presence of LBs. This review summarizes results obtained with patients, mouse models, and cell lines and consolidates apparent paradoxes in the LD literature. Based on the growing body of evidence, it proposes that LD is predominantly caused by an impairment in chain-length regulation affecting only a small proportion of the cellular glycogen. A better grasp of LD pathogenesis will further develop our understanding of glycogen metabolism and structure. It will also facilitate the development of clinical interventions that appropriately target the underlying cause of LD. View Full-Text
Keywords: lafora disease; laforin; malin; polyglucosan body; chain length distribution; glycogen phosphorylation lafora disease; laforin; malin; polyglucosan body; chain length distribution; glycogen phosphorylation
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MDPI and ACS Style

Sullivan, M.A.; Nitschke, S.; Steup, M.; Minassian, B.A.; Nitschke, F. Pathogenesis of Lafora Disease: Transition of Soluble Glycogen to Insoluble Polyglucosan. Int. J. Mol. Sci. 2017, 18, 1743.

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