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The malin‐laforin compex modulates glycogen catabolism through its effect on glycogen phosphorylase
Author(s) -
Dukhande Vikas V,
Paasch Bradley,
Gentry Matthew S
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.662.6
Subject(s) - lafora disease , glycogen , glycogen phosphorylase , glycogen synthase , progressive myoclonus epilepsy , catabolism , knockout mouse , biology , glycogen debranching enzyme , gsk3b , endocrinology , ubiquitin ligase , medicine , biochemistry , phosphorylation , phosphatase , ubiquitin , metabolism , gsk 3 , gene
Autosomal recessive mutations in genes encoding malin or laforin cause Lafora disease (LD). LD is a progressive myoclonic epilepsy characterized by pathological aberrant glycogen accumulations in brain and various other organs. Laforin is a novel glycogen phosphatase essential for maintaining glycogen in a soluble form. Malin, a RING‐type E3 ubiquitin ligase, is known to ubiquitinate proteins involved in glycogen metabolism. However, malin's role in LD pathogenesis is not clear. In this study, we aimed to discover malin substrate and define their function in LD pathogenesis. We used malin knockout and laforin knockout mice, immunoprecipitation, western analysis, immunocytochemistry, glucan‐binding assay, PAS staining and enzyme activity measurements. We discovered glycogen phosphorylase (GP) as a novel substrate of malin. GP is vital in catabolism of cellular glycogen. The expression of GP was decreased in liver and skeletal muscle tissues from malin knockout mice. Our data suggest that malin does not target GP for proteasomal degradation. Instead, we found that malin interacted with GP and increased nuclear localization of GP. Malin also altered the glucan‐binding and phosphorylation of GP. Thus, our data show that GP is a novel substrate of malin. Further exploration into the mechanisms of this regulation will unravel insights in glycogen metabolism, physiological functions of the malin‐laforin complex and will aid in betterment of LD pharmacotherapy. Supported by NIH grants R00NS061803, R01NS070899 and University of Kentucky College of Medicine startup funds to MSG and AHA Great Rivers Affiliate Postdoctoral fellowship to VVD.