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

10 Scopus citations

Abstract

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 languageAmerican English
Article numbere14554
JournalEMBO Molecular Medicine
Volume13
Issue number10
DOIs
StatePublished - 7 Oct 2021

Bibliographical note

Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY 4.0 license

Keywords

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

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