Journal Article

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

Chown, Erin E, Zhao, Xiaochu, Minassian, Berge A, Nitschke, Felix, Sullivan, Mitchell A, Rodríguez de Córdoba, Santiago, Perri, Ami M, Bovolenta, Paola, Wang, Peixiang, Israelian, Lori, Steup, Martin, Juana‐López, Lucia

2017

Overview

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. Synopsis Abnormal glycogen chain length distribution strictly correlates with glycogen accumulation and Lafora body (LB) formation in Lafora disease (LD). Against current hypotheses, neither glycogen hyperphosphorylation nor deficient general autophagy are prerequisites of the disease. By methodological advances chain length distribution (CLD) and phosphorylation of glycogen were determined in brain tissue confirming that overexpressed wild‐type laforin corrects the molecular phenotype in an LD mouse model. Phosphatase‐inactive laforin does not correct glycogen hyperphosphorylation in malin‐ and laforin‐deficient mice and prevents abnormal CLD and accumulation of glycogen as well as LB formation. Prevention of abnormal chain length distribution and accumulation of brain glycogen as well as LB formation by phosphatase‐inactive laforin is malin‐dependent as no rescue occurs in malin‐deficient mice. General impairment of autophagy is not necessary in LD as markers of autophagic flux are not changed in any of our LD mouse models. Laforin controls glycogen chain length distribution in a malin‐dependent fashion, and lack of this control leads to abnormal glycogen structure, glycogen accumulation, LB formation, hence to LD. Graphical Abstract Abnormal glycogen chain length distribution strictly correlates with glycogen accumulation and Lafora body (LB) formation in Lafora disease (LD). Against current hypotheses, neither glycogen hyperphosphorylation nor deficient general autophagy are prerequisites of the disease.

• Publisher: Nature Publishing Group UK,John Wiley & Sons, Inc,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Analysis / Animal models / Animals / Autophagy / Brain - pathology / Disease Models, Animal / Dual-Specificity Phosphatases - deficiency / Dual-Specificity Phosphatases - metabolism / EMBO16 / EMBO21 / EMBO27 / Epilepsy / Female / Glycogen / Glycogen - chemistry / Glycogen - metabolism / glycogen chain length / glycogen phosphorylation / Lafora disease / Lafora Disease - pathology / laforin / Male / malin / Mice, Inbred C57BL / Molecular Weight / Neurotoxicity / Phagocytosis / Phosphatase / Phosphatases / Phosphates / Phosphorylation / Protein Tyrosine Phosphatases, Non-Receptor / Research Article / Rodents / Ubiquitin / Ubiquitin-protein ligase / Ubiquitin-Protein Ligases - deficiency / Ubiquitin-Protein Ligases - metabolism