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Glycogen hyperphosphorylation underlies lafora body formation
Author(s) -
Turnbull Julie,
Wang Peixiang,
Girard JeanMarie,
Ruggieri Alessandra,
Wang Tony J.,
Draginov Arman G.,
Kameka Alexander P.,
Pencea Nela,
Zhao Xiaochu,
Ackerley Cameron A.,
Minassian Berge A.
Publication year - 2010
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22156
Subject(s) - lafora disease , glycogen , glycogen branching enzyme , glycogen synthase , progressive myoclonus epilepsy , endocrinology , biology , gsk3b , medicine , glycogen debranching enzyme , hyperphosphorylation , biochemistry , phosphatase , gsk 3 , phosphorylation , gene
Objective: Glycogen, the largest cytosolic macromolecule, acquires solubility, essential to its function, through extreme branching. Lafora bodies are aggregates of polyglucosan, a long, linear, poorly branched, and insoluble form of glycogen. Lafora bodies occupy vast numbers of neuronal dendrites and perikarya in Lafora disease in time‐dependent fashion, leading to intractable and fatal progressive myoclonus epilepsy. Lafora disease is caused by deficiency of either the laforin glycogen phosphatase or the malin E3 ubiquitin ligase. The 2 leading hypotheses of Lafora body formation are: (1) increased glycogen synthase activity extends glycogen strands too rapidly to allow adequate branching, resulting in polyglucosans; and (2) increased glycogen phosphate leads to glycogen conformational change, unfolding, precipitation, and conversion to polyglucosan. Recently, it was shown that in the laforin phosphatase‐deficient form of Lafora disease, there is no increase in glycogen synthase, but there is a dramatic increase in glycogen phosphate, with subsequent conversion of glycogen to polyglucosan. Here, we determine whether Lafora bodies in the malin ubiquitin ligase‐deficient form of the disease are due to increased glycogen synthase or increased glycogen phosphate. Methods: We generated malin‐deficient mice and tested the 2 hypotheses. Results: Malin‐deficient mice precisely replicate the pathology of Lafora disease with Lafora body formation in skeletal muscle, liver, and brain, and in the latter in the pathognomonic perikaryal and dendritic locations. Glycogen synthase quantity and activity are unchanged. There is a highly significant increase in glycogen phosphate. Interpretation: We identify a single common modification, glycogen hyperphosphorylation, as the root cause of Lafora body pathogenesis. ANN NEUROL, 2010