Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease

Nitschke, Felix, Sullivan, Mitchell A., Wang, Peixiang, Zhao, Xiaochu, Chown, Erin E., Perri, Ami M., Israelian, Lori, Juana-Lopez, Lucia, Bovolenta, Paola, Rodriguez de Cordoba, Santiago, Steup, Martin and Minassian, Berge A. (2017) Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease. EMBO Molecular Medicine, 9 7: 906-917. doi:10.15252/emmm.201707608

Author Nitschke, Felix
Sullivan, Mitchell A.
Wang, Peixiang
Zhao, Xiaochu
Chown, Erin E.
Perri, Ami M.
Israelian, Lori
Juana-Lopez, Lucia
Bovolenta, Paola
Rodriguez de Cordoba, Santiago
Steup, Martin
Minassian, Berge A.
Title Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease
Journal name EMBO Molecular Medicine   Check publisher's open access policy
ISSN 1757-4684
Publication date 2017-07-01
Sub-type Article (original research)
DOI 10.15252/emmm.201707608
Open Access Status DOI
Volume 9
Issue 7
Start page 906
End page 917
Total pages 12
Place of publication Weinheim, Germany
Publisher Wiley - V C H Verlag GmbH & Co. KGaA
Language eng
Subject 1313 Molecular Medicine
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.
Keyword Glycogen chain length
Glycogen phosphorylation
Lafora disease
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID GNT1092451
P01 NS097197
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Mater Research Institute-UQ (MRI-UQ)
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