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nitschke-et-al-2017-abnormal-glycogen-chain-length-pattern-not-hyperphosphorylation-is-critical-in-lafora-disease1.43 MB
Published VersionCC BY V4.0, Open Access
Journal article
Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease
EMBO Molecular Medicine, Vol.9(7), pp.906-917
2017
PMID: 28536304
Abstract
Lafora disease (LD) is a fatal progressive epilepsy essentially caused by loss-of-function mutations in the glycogen phosphatase laforin or the ubiquitin E3 ligase malin. Glycogen in LD is hyperphosphorylated and poorly hydrosoluble. It precipitates and accumulates into neurotoxic Lafora bodies (LBs). The leading LD hypothesis that hyperphosphorylation causes the insolubility was recently challenged by the observation that phosphatase-inactive laforin rescues the laforin-deficient LD mouse model, apparently through correction of a general autophagy impairment. We were for the first time able to quantify brain glycogen phosphate. We also measured glycogen content and chain lengths, LBs, and autophagy markers in several laforin- or malin-deficient mouse lines expressing phosphatase-inactive laforin. We find that: (i) in laforin-deficient mice, phosphatase-inactive laforin corrects glycogen chain lengths, and not hyperphosphorylation, which leads to correction of glycogen amounts and prevention of LBs; (ii) in malin-deficient mice, phosphatase-inactive laforin confers no correction; (iii) general impairment of autophagy is not necessary in LD We conclude that laforin's principle function is to control glycogen chain lengths, in a malin-dependent fashion, and that loss of this control underlies LD.
Details
- Title
- Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease
- Authors
- Felix Nitschke - Hospital for Sick ChildrenMitchell A Sullivan - Hospital for Sick ChildrenPeixiang Wang - Hospital for Sick ChildrenXiaochu Zhao - Hospital for Sick ChildrenErin E Chown - Hospital for Sick ChildrenAmi M Perri - Hospital for Sick ChildrenLori Israelian - Hospital for Sick ChildrenLucia Juana‐López - Centro de Biología Molecular Severo OchoaSantiago Rodríguez de Córdoba - Centro de Investigaciones Biológicas Margarita SalasMartin Steup - Hospital for Sick ChildrenBerge A Minassian - Hospital for Sick Children
- Publication details
- EMBO Molecular Medicine, Vol.9(7), pp.906-917
- Publisher
- EMBO Press
- Date published
- 2017
- DOI
- 10.15252/emmm.201707608
- ISSN
- 1757-4684; 1757-4676
- PMID
- 28536304
- Copyright note
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Organisation Unit
- School of Health - Biomedicine
- Language
- English
- Record Identifier
- 991035097002621
- Output Type
- Journal article
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