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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.

Lafora disease (LD) is an intractable, neurodegenerative epilepsy caused by loss-of-function mutations in the EPM2A or EPM2B genes. Central to LD is the accumulation of malstructured glycogen (Lafora bodies; LB) in neurons, a consequence of dysregulated glycogen synthesis. Glycogen synthase catalyzes glycogen formation and is activated by dephosphorylation. The latter is mediated by glycogen-targeting subunits of protein phosphatase 1, including PTG (R5) and R6, known formally as PPP1R3D, both abundantly expressed in brain. PTG knockout in LD mice rescues LD, including near-complete disappearance of LB and neurodegeneration. I examined whether the same could be achieved with R6 knockout. Despite significant brain glycogen and LB reductions in R6-deficient-Epm2a-/- mice, substantial amounts of LB remained and neurodegeneration was not rescued. This partial effect remains unexplained. Future experiments to resolve the difference with PTG will shed important light on both LB formation and Lafora disease, and brain glycogen metabolism.

Mis‐secreted glycoproteins (LGI1, reelin) are emerging causes of epilepsy. LMAN2L belongs to a glycoprotein secretion chaperone family. One recessive LMAN2L missense mutation predicted to impair the chaperone's interaction with glycoproteins was reported in a family with intellectual disability (ID) and remitting epilepsy. We describe four members of a family with autosomal dominant inheritance of a similar phenotype. We show that they segregate a NM_001142292.1:c.1073delT mutation that eliminates LMAN2L's endoplasmic reticulum retention signal and mislocalizes the protein from that compartment to the plasma membrane. LMAN2L mislocalization, like impaired glycoprotein interaction, disturbs brain development, including generation of developmentally restricted epilepsy.

Glycogen synthesis is vital, malstructure resulting in precipitation and accumulation into neurotoxic polyglucosan bodies (PBs). One well-understood mechanism of PB generation is glycogen branching enzyme deficiency (GBED). Less understood is Lafora disease (LD), resulting from absence of the glycogen phosphatase laforin or the E3 ubiquitin ligase malin, and accumulation of hyperphosphorylated PBs. LD afforded first insight that glycogen sphericity depends on more than adequate branching activity. Unexpectedly, deficiencies of the Linear Ubiquitin Chain Assembly Complex (LUBAC) components RBCK1 and HOIP result in PBs in muscle tissues. Here we analyzed nervous system phenotypes of mice lacking RBCK1 and find profuse PB accumulations in brain and spinal cord with extensive neurodegeneration and neurobehavioral deficits. Brain glycogen in these mice is characterized by long chains and hyperphosphorylation, similar to LD. Like in LD, glycogen synthase and branching enzyme are unaltered. Regional PB distribution mirrors LD and not GBED. Perisynaptic PB localization is unlike LD or GBED. The results indicate that RBCK1 is part of a system supplementing laforin-malin in regulating glycogen architecture including in unique neuronal locales.