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Comment
. 2022 Apr;19(3):977-981.
doi: 10.1007/s13311-022-01240-9. Epub 2022 Apr 22.

Two Diseases-One Preclinical Treatment Targeting Glycogen Synthesis

Matthew S Gentry  1 , Kia H Markussen  2 , Katherine J Donohue  2
Affiliations
Comment

Two Diseases-One Preclinical Treatment Targeting Glycogen Synthesis

Matthew S Gentry et al. Neurotherapeutics. 2022 Apr.
No abstract available

Keywords: AAV9; Adult polyglucosan body disease; Glycogen; Glycogen storage disease; Lafora disease; Neurodegeneration.

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Figures

Fig. 1
Fig. 1
Representation of polyglucosan body formation. Glycogen is synthesized by the combined activity of glycogen synthase (GYS1) and glycogen branching enzyme (GBE) and it is degraded by glycogen phosphorylase (PYGB, brain isoform) and glycogen debranching enzyme (GDE). Lafora disease (LD) and adult polyglucosan body disease (APBD) patients and mouse models exhibit aberrant, glycogen-like aggregates called polyglucosan bodies. When glycogen synthesis is reduced in LD or APBD, polyglucosan body levels are reduced
Fig. 2
Fig. 2
Glycogen metabolism. A Summary of major steps of glycogen metabolism. Glucose enters cells via a glucose transporter (Glut1) and is phosphorylated by hexokinase (HK) to generate glucose-6-phosphate (G6P). G6P is converted into glucose-1-phosphate by phosphoglucomutase (PGM) and then to UDP-glucose (UDP-Glc) by UDP-glucose pyrophosphorylase (UGP). Glycogen synthase (GYS1) and glycogen branching enzyme (GBE) catalyze glucose chains and branching, respectively, to synthesize glycogen. Glycogen is catabolized by the sequential removal of G1P monomers via glycogen phosphorylase (PYGB) with glycogen debranching enzyme (GDE) removing branch points. Adult polyglucosan body disease (APBD) is caused by mutations in GBE. B Lafora disease (LD) is caused by autosomal recessive mutations in the gene encoding laforin or malin. Laforin is a glycogen phosphatase that removes phosphate from glycogen (component 1). Malin is an E3 ubiquitin ligase that forms a complex with laforin and ubiquitinates a number of enzymes that synthesize or catabolize glycogen (component 2). Perturbed laforin or malin activity results in aberrant glycogen metabolism and PGB formation, and PGBs drive LD progression
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