Glycogen storage in a zebrafish Pompe disease model is reduced by 3-BrPA treatment

Bragato, C., Carra, S., Blasevich, F., Salerno, F., Brix, A., Bassi, A., Beltrame, M., Cotelli, F., Maggi, L., Mantegazza, R., Mora, M.
Biochimica et biophysica acta. Molecular basis of disease   1866(5): 165662 (Journal)
Registered Authors
Beltrame, Monica, Cotelli, Franco
3-Bromopyruvic acid (3-BrPA), Acid α-glucosidase, Glycogen, Pompe disease, Zebrafish
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Autophagy/drug effects
  • Drug Evaluation, Preclinical
  • Gene Knockdown Techniques
  • Glycogen/metabolism*
  • Glycogen Storage Disease Type II/drug therapy*
  • Glycogen Storage Disease Type II/genetics
  • Glycogen Storage Disease Type II/pathology
  • Glycolysis/drug effects
  • Hexokinase/antagonists & inhibitors*
  • Hexokinase/metabolism
  • Humans
  • Lysosomes
  • Microscopy, Electron
  • Morpholinos/administration & dosage
  • Morpholinos/genetics
  • Motor Activity/drug effects
  • Muscle, Skeletal/drug effects
  • Muscle, Skeletal/metabolism
  • Muscle, Skeletal/pathology
  • Muscle, Skeletal/ultrastructure
  • Pyruvates/pharmacology*
  • Pyruvates/therapeutic use
  • Zebrafish
  • Zebrafish Proteins/antagonists & inhibitors
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • alpha-Glucosidases/genetics
  • alpha-Glucosidases/metabolism
31917327 Full text @ BBA Molecular Basis of Disease
Pompe disease (PD) is an autosomal recessive muscular disorder caused by deficiency of the glycogen hydrolytic enzyme acid α-glucosidase (GAA). The enzyme replacement therapy, currently the only available therapy for PD patients, is efficacious in improving cardiomyopathy in the infantile form, but not equally effective in the late onset cases with involvement of skeletal muscle. Correction of the skeletal muscle phenotype has indeed been challenging, probably due to concomitant dysfunctional autophagy. The increasing attention to the pathogenic mechanisms of PD and the search of new therapeutic strategies prompted us to generate and characterize a novel transient PD model, using zebrafish. Our model presented increased glycogen content, markedly altered motor behavior and increased lysosome content, in addition to altered expression of the autophagy-related transcripts and proteins Beclin1, p62 and Lc3b. Furthermore, the model was used to assess the beneficial effects of 3-bromopyruvic acid (3-BrPA). Treatment with 3-BrPA induced amelioration of the model phenotypes regarding glycogen storage, motility behavior and autophagy-related transcripts and proteins. Our zebrafish PD model recapitulates most of the defects observed in human patients, proving to be a powerful translational model. Moreover, 3-BrPA unveiled to be a promising compound for treatment of conditions with glycogen accumulation.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes