Glycogen Phosphomonoester Distribution in Mouse Models of the Progressive Myoclonic Epilepsy, Lafora Disease

Abstract

Background: Lafora disease is characterized by abnormal, hyperphosphorylated glycogen. Results: 20% of the total phosphate is present as a C6 phosphomonoester of glucose residues; this proportion is unchanged in glycogen from mouse models of Lafora disease. Conclusion: C6 phosphate is not the dominant phosphomonoester. Significance: C2, C3, or C6 phosphate could all contribute to aberrant glycogen structure.

Muscle Glycogen Remodeling and Glycogen Phosphate Metabolism following Exhaustive Exercise of Wild Type and Laforin Knockout Mice

“…The estimate was that this reaction occurred once every 10,000 catalytic cycles. Although this mechanism could explain the formation of C2-and possibly C3-phosphomonesters, it is unlikely to account for the C6 phosphate observed in glycogen (10,11). This mechanism has been challenged by Nitschke et al (10) who claimed that our measurement of glycogen phosphorylation was the result of [ 32 P]UDP binding to glycogen.…”

“…In the present study of young mice, the absence of laforin, with the consequent hyper-phosphorylation of glycogen, led to delayed restoration of the native structure to glycogen during recovery from exercise, affirming an interrelationship between phosphorylation and branching. Although phosphorylation of glucose residues in glycogen could directly affect the chemistry and/or enzymology of branching at specific glucose residues, the frequency of phosphorylation, even in glycogen from aged Lafora mice, is so low as to make it hard to envision a reduction in overall branching based on this mechanism (11). Also, it is important to distinguish young versus old laforin knock-out mice.…”

Myocardial autophagic energy stress responses—macroautophagy, mitophagy, and glycophagy

“…Glycogen phosphorylation may compromise glycogen solubility indirectly by interfering with intermolecular bonds between adjacent branches, or directly by preventing branching due to phosphorylation at C6 of the glucose residues. Understanding of how excess glycogen phosphorylation confers macromolecular solubility is limited; however, recent evidence suggests that this phosphorylation is a regulated process (9,69). Overexpression of laforin has been shown to augment autophagy (1).…”

Incorporation of phosphate into glycogen by glycogen synthase

“…Measurements of the abundance of the phosphate have ranged from ~1:500 to ~1:5000 phosphates per glucose residue and depend on the source of the glycogen. Recent studies suggest that the phosphate exists as monoesters at C2, C3 and C6 carbons of glucose residues within the glycogen [6, 7]. Plant amylopectin, which is a close relative of glycogen both chemically and functionally, also contains C3 and C6 phosphomonoesters of glucose [8-11].…”

“…Laforin, which by sequence can be placed in the sub-family of atypical dual specificity protein phosphatases [22], has been shown to dephosphorylate amylopectin [23, 24], glycogen [24], and phospho-oligosaccharides in vitro [25]. Furthermore, glycogen isolated from laforin or malin knockout mice has an elevated phosphate content [6, 24, 26] and, with aging, the glycogen becomes less branched and less water soluble, consistent with the formation of Lafora bodies [12]. Therefore, laforin appears to act as a glycogen phosphatase in vivo and its absence results in abnormal glycogen structure which may underlie the pathology of Lafora disease.…”