Comparative proteomics of APBD and heathy control cells treated or not with 144DG11 under different conditions

ABSTRACT: This project 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. The results submitted to Pride are the raw LC-MS proteomics data of skin fibroblasts derived from APBD and healthy control subjects treated or not with 144DG11 under starvation or glycogen burden (starvation followed by glucose supplementation) conditions.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skin, Fibroblast

DISEASE(S): Glycogen Storage Disease Iv

SUBMITTER: Or Kakhlon  

LAB HEAD: Or Kakhlon

PROVIDER: PXD027583 | Pride | 2022-02-17

REPOSITORIES: Pride