Alleviation of a polyglucosan storage disorder by enhancement of autophagic glycogen catabolism

Or Kakhlon*, Hilla Vaknin, Kumudesh Mishra, Jeevitha D’Souza, Monzer Marisat, Uri Sprecher, Shane Wald-Altman, Anna Dukhovny, Yuval Raviv, Benny Da’adoosh, Hamutal Engel, Sandrine Benhamron, Keren Nitzan, Sahar Sweetat, Anna Permyakova, Anat Mordechai, Hasan Orhan Akman, Hanna Rosenmann, Alexander Lossos, Joseph TamBerge A. Minassian, Miguel Weil

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


This work employs adult polyglucosan body disease (APBD) models to explore the efficacy and mechanism of action of the polyglucosan-reducing compound 144DG11. APBD is a glycogen storage disorder (GSD) caused by glycogen branching enzyme (GBE) deficiency causing accumulation of poorly branched glycogen inclusions called polyglucosans. 144DG11 improved survival and motor parameters in a GBE knockin (Gbeys/ys) APBD mouse model. 144DG11 reduced polyglucosan and glycogen in brain, liver, heart, and peripheral nerve. Indirect calorimetry experiments revealed that 144DG11 increases carbohydrate burn at the expense of fat burn, suggesting metabolic mobilization of pathogenic polyglucosan. At the cellular level, 144DG11 increased glycolytic, mitochondrial, and total ATP production. The molecular target of 144DG11 is the lysosomal membrane protein LAMP1, whose interaction with the compound, similar to LAMP1 knockdown, enhanced autolysosomal degradation of glycogen and lysosomal acidification. 144DG11 also enhanced mitochondrial activity and modulated lysosomal features as revealed by bioenergetic, image-based phenotyping and proteomics analyses. As an effective lysosomal targeting therapy in a GSD model, 144DG11 could be developed into a safe and efficacious glycogen and lysosomal storage disease therapy.

Original languageEnglish
Article numbere14554
JournalEMBO Molecular Medicine
Issue number10
StatePublished - 7 Oct 2021


FundersFunder number
Israel Innovation Authority Kamin61224
Israel Ministry of Science and Technology Personalized Medicine60300
Krigsner Foundation
Orphan Disease CenterMDBR‐20‐100‐APBD, MDBR‐19‐134‐APBD
National Institute of Neurological Disorders and StrokeP01NS097197


    • adult polyglucosan body disease
    • autophagy
    • glycogen
    • lysosomes
    • polyglucosan


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