Laforin and Malin: Novel Regulators of Glycogen Metabolism

Abstract

Lafora disease (LD) is an autosomal recessive neurodegenerative disease that results in progressive myoclonus epilepsy and death. LD is caused by mutations in either the E3 ubiquitin ligase, malin, or the dual‐specificity phosphatase, laforin. A hallmark of LD is the accumulation of insoluble complex carbohydrates similar to amylopectin in the cytoplasm of cells from most tissues. Classically, glycogen metabolism was shown to be regulated by phosphorylation of key metabolic enzymes. One regulator of phosphorylation status is protein targeting to glycogen (PTG/R5), a scaffold protein that binds glycogen and many of enzymes involved in glycogen metabolism, including protein phosphatase 1 (PP1), glycogen synthase, phosphorylase, and laforin. Overexpression of PTG markedly increases glycogen accumulation, and decreased PTG expression decreases glycogen stores. To investigate if malin and laforin play a role in glycogen metabolism, we overexpressed PTG, malin, and laforin in tissue culture cells. We found that expression of malin or laforin decreased PTG‐stimulated glycogen accumulation by 25%, and co‐expression of malin and laforin abolished PTG‐stimulated glycogen accumulation. Consistent with this result, we found that malin ubiquitinates PTG in a laforin‐dependent manner, both in vivo and in vitro, and targets PTG for proteasome‐dependent degradation. These results suggest a novel mechanism, involving laforin and malin, in regulating glycogen metabolism.