Glycogen hyperphosphorylation underlies lafora body formation
Article first published online: 12 NOV 2010
Copyright © 2010 American Neurological Association
Annals of Neurology
Volume 68, Issue 6, pages 925–933, December 2010
How to Cite
Turnbull, J., Wang, P., Girard, J.-M., Ruggieri, A., Wang, T. J., Draginov, A. G., Kameka, A. P., Pencea, N., Zhao, X., Ackerley, C. A. and Minassian, B. A. (2010), Glycogen hyperphosphorylation underlies lafora body formation. Ann Neurol., 68: 925–933. doi: 10.1002/ana.22156
- Issue published online: 30 DEC 2010
- Article first published online: 12 NOV 2010
- Accepted manuscript online: 28 OCT 2010 07:27AM EST
- Manuscript Accepted: 9 JUL 2010
- Manuscript Revised: 2 JUL 2010
- Manuscript Received: 22 JUN 2010
- Natural Sciences and Engineering Research Council of Canada Graduate Scholarship
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.
We generated malin-deficient mice and tested the 2 hypotheses.
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.
We identify a single common modification, glycogen hyperphosphorylation, as the root cause of Lafora body pathogenesis. ANN NEUROL, 2010