Relationship between glycogen accumulation and the laforin dual specificity phosphatase.
Laforin, encoded by the EPM2A gene, is a dual specificity protein phosphatase that has a functional glycogen-binding domain. Mutations in the EPM2A gene account for around half of the cases of Lafora disease, an autosomal recessive neurodegenerative disorder, characterized by progressive myoclonus epilepsy. The hallmark of the disease is the presence of Lafora bodies, which contain polyglucosan, a poorly branched form of glycogen, in neurons and other tissues. We examined the level of laforin protein in several mouse models in which muscle glycogen accumulation has been altered genetically. Mice with elevated muscle glycogen have increased laforin as judged by Western analysis. Mice completely lacking muscle glycogen or with 10% normal muscle glycogen had reduced laforin. Mice defective in the GAA gene encoding lysosomal alpha-glucosidase (acid maltase) overaccumulate glycogen in the lysosome but did not have elevated laforin. We propose, therefore, that laforin senses cytosolic glycogen accumulation which in turn determines the level of laforin protein.
Wang
Wei
W
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5122, USA.
Parker
Gretchen E
GE
Skurat
Alexander V
AV
Raben
Nina
N
DePaoli-Roach
Anna A
AA
Roach
Peter J
PJ
D000818:Animals; D004195:Disease Models, Animal; D054637:Dual-Specificity Phosphatases; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006003:Glycogen / Q000235:genetics / Q000378:metabolism*; D020192:Lafora Disease / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D054558:Protein Tyrosine Phosphatases, Non-Receptor
D006003:Glycogen; D010744:Phosphoric Monoester Hydrolases; D054637:Dual-Specificity Phosphatases; C491989:Epm2a protein, mouse; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor