Open AccessAlleviation of a polyglucosan storage disorder by enhancement of autophagic glycogen catabolism
Author(s) -
Kakhlon Or,
Vaknin Hilla,
Mishra Kumudesh,
D’Souza Jeevitha,
Marisat Monzer,
Sprecher Uri,
WaldAltman Shane,
Dukhovny Anna,
Raviv Yuval,
Da’adoosh Benny,
Engel Hamutal,
Benhamron Sandrine,
Nitzan Keren,
Sweetat Sahar,
Permyakova Anna,
Mordechai Anat,
Akman Hasan Orhan,
Rosenmann Hanna,
Lossos Alexander,
Tam Joseph,
Minassian Berge A.,
Weil Miguel
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202114554
Subject(s) - glycogen , lamp1 , autophagy , glycolysis , substrate reduction therapy , glycogen branching enzyme , lysosome , catabolism , glycogen synthase , enzyme replacement therapy , mitochondrion , chemistry , biochemistry , microbiology and biotechnology , endocrinology , biology , medicine , metabolism , enzyme , apoptosis , disease
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 (Gbe ys/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.