title: Hyperphosphorylation of glucosyl C6 carbons and altered structure of glycogen in the neurodegenerative epilepsy Lafora disease.
abstract: Laforin or malin deficiency causes Lafora disease, characterized by altered glycogen metabolism and teenage-onset neurodegeneration with intractable and invariably fatal epilepsy. Plant starches possess small amounts of metabolically essential monophosphate esters. Glycogen contains similar phosphate amounts, which are thought to originate from a glycogen synthase error side reaction and therefore lack any specific function. Glycogen is also believed to lack monophosphates at glucosyl carbon C6, an essential phosphorylation site in plant starch metabolism. We now show that glycogen phosphorylation is not due to a glycogen synthase side reaction, that C6 is a major glycogen phosphorylation site, and that C6 monophosphates predominate near centers of glycogen molecules and positively correlate with glycogen chain lengths. Laforin or malin deficiency causes C6 hyperphosphorylation, which results in malformed long-chained glycogen that accumulates in many tissues, causing neurodegeneration in brain. Our work advances the understanding of Lafora disease pathogenesis and suggests that glycogen phosphorylation has important metabolic function.
authors.affiliation: Institute of Biochemistry and Biology, University of Potsdam, Karl-Liebknecht-Strasse 24-25, 14476 Potsdam-Golm, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Nitschke
authors.forename: Peixiang
authors.initials: P
authors.lastname: Wang
authors.forename: Peter
authors.initials: P
authors.lastname: Schmieder
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Girard
authors.forename: Donald E
authors.initials: DE
authors.lastname: Awrey
authors.forename: Tony
authors.initials: T
authors.lastname: Wang
authors.forename: Johan
authors.initials: J
authors.lastname: Israelian
authors.forename: XiaoChu
authors.initials: X
authors.lastname: Zhao
authors.forename: Julie
authors.initials: J
authors.lastname: Turnbull
authors.forename: Matthias
authors.initials: M
authors.lastname: Heydenreich
authors.forename: Erich
authors.initials: E
authors.lastname: Kleinpeter
authors.forename: Martin
authors.initials: M
authors.lastname: Steup
authors.forename: Berge A
authors.initials: BA
authors.lastname: Minassian
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D002244:Carbon / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism*; D006006:Glycogen Synthase / Q000378:metabolism; D020192:Lafora Disease / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D010766:Phosphorylation; D011817:Rabbits
chemical_list: D002244:Carbon; D006003:Glycogen; D006006:Glycogen Synthase