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Published VersionCC BY V4.0, Open Access
Journal article
Pathogenesis of Lafora Disease: Transition of Soluble Glycogen to Insoluble Polyglucosan
International Journal of Molecular Sciences, Vol.18(8), pp.1-17
2017
PMID: 28800070
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
(laforin) or
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.
Details
- Title
- Pathogenesis of Lafora Disease: Transition of Soluble Glycogen to Insoluble Polyglucosan
- Authors
- Mitchell A Sullivan - Hospital for Sick ChildrenSilvia Nitschke - Hospital for Sick ChildrenMartin Steup - Hospital for Sick ChildrenBerge A Minassian - Hospital for Sick ChildrenFelix Nitschke (Corresponding Author) - Hospital for Sick Children
- Publication details
- International Journal of Molecular Sciences, Vol.18(8), pp.1-17
- Publisher
- MDPI AG
- Date published
- 2017
- DOI
- 10.3390/ijms18081743
- ISSN
- 1422-0067; 1661-6596
- PMID
- 28800070
- Copyright note
- © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
- Organisation Unit
- School of Health - Biomedicine
- Language
- English
- Record Identifier
- 991035096802621
- Output Type
- Journal article
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- Web Of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Multidisciplinary
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