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

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.

Imprinted cell memory in glycogen storage disorder 1a

“…Importantly, the metabolic regulator Sirt-1 pathway, dependent on NAD + availability, is clearly upregulated in the presence of GHF201 which impacts on both the mitochondrial and lysosomal branches. Knowing that GHF201 targets the lysosomal marker LAMP-1 and in turn reduces glycogen accumulation (see difference in glycogen metabolite node size between groups) it becomes apparent that the compound's effect is mostly associated with the lysosomal-autophagy axis as previously demonstrated in APBD models 13 . This autophagy promoting activity might directly increase the ETC rate and ATP production, which in turn improves NAD + /NADH ratio (see Figure 4) activating Sirt-1 deacetylase activity in the GSD1a disease phenotype.…”

“…Lysosomal pH ratiometric measuring. Ratiometric analysis of Lysosensor dye labeling for lysosomal pH was analyzed using ratiomeric fluorimetry by confocal microscopy analysis as described previously 13 .…”

“…For this purpose, skin fibroblasts from GSD1a patients and HC (age and gender matched) individuals were incubated for 24 h and 48 h in cell culture media under serum and glucose starvation and for 72 h where full medium (with serum and glucose) was restored for the last 24 h of incubation. These different culture conditions were used to induce metabolic stress in the cells caused by sugar deprivation (24 and 48 h) and consecutive glycogen burden caused by adding back sugar to the media for 24 h (72 h), which proved to be highly effective in describing the GSD phenotype as shown in similar, previously published HCA phenotyping experiments of APBD (GSD-IV) patients' fibroblasts 13 .…”

Pathomorphogenesis of Glycogen-Ground Glass Hepatocytic Inclusions (Polyglucosan Bodies) in Children after Liver Transplantation

“…This, however, is not sufficient to suggest variations in the treatment, as the main purpose of clinical transplants is to save the graft rather than preventing transient, non-progressive histological changes. Likewise, while it seems reasonable to try to alleviate the irreversible permanent PG storage in secondary glycogen storage disease (SGSD) by using molecules that bind to the lysosomal membrane protein (LAMP-1) [ 26 ] in order to enhance autophagic glycogen catabolism [ 27 ], this would not be recommended for a non-progressive and reversible lesion such as drug-induced GGG.…”

Novel Gene-Correction-Based Therapeutic Modalities for Monogenic Liver Disorders

“…GSD IV (also known as Anderson disease) is caused by abnormal glycogen accumulation because of the decreased activity of glycogen branching enzyme (GBE) [ 224 ]. Akman and colleagues developed a Gbe1 ys/ys mouse model [ 225 ] and Yi and co-workers used the recipient for AAV9 containing the GBE human expression cassette (AAV-GBE). Evaluation of the effectiveness of gene therapy in GSD IV showed that AAV treatment reduced damage and improved liver performance and muscle functions [ 226 ].…”