N-butyldeoxynojirimycin treatment restores the innate fear response and improves learning in mucopolysaccharidosis IIIA mice

Mol Genet Metab. 2016 Jun;118(2):100-10. doi: 10.1016/j.ymgme.2016.04.002. Epub 2016 Apr 13.


Mucopolysaccharidosis IIIA is a heritable neurodegenerative disorder resulting from the dysfunction of the lysosomal hydrolase sulphamidase. This leads to the primary accumulation of the complex carbohydrate heparan sulphate in a wide range of tissues and the secondary neuronal storage of gangliosides GM2 and GM3 in the brain. GM2 storage is associated with CNS deterioration in the GM2 gangliosidosis group of lysosomal storage disorders and may also contribute to MPS CNS disease. N-butyldeoxynojirimycin, an inhibitor of ceramide glucosyltransferase activity and therefore of ganglioside synthesis, was administered to MPS IIIA mice both prior to maximal GM2 and GM3 accumulation (early treatment) and after the maximum level of ganglioside had accumulated in the brain (late treatment) to determine if behaviour was altered by ganglioside level. Ceramide glucosyltransferase activity was decreased in both treatment groups; however, brain ganglioside levels were only decreased in the late treatment group. Learning in the water cross maze was improved in both groups and the innate fear response was also restored in both groups. A reduction in the expression of inflammatory gene Ccl3 was observed in the early treatment group, while IL1β expression was reduced in both treatment groups. Thus, it appears that NB-DNJ elicits a transient decrease in brain ganglioside levels, some modulation of inflammatory cytokines and a functional improvement in behaviour that can be elicited both before and after overt neurological changes manifest.

Synopsis: NB-DNJ improves learning and restores the innate fear response in MPS IIIA mice by decreasing ceramide glucosyltransferase activity and transiently reducing ganglioside storage and/or modulating inflammatory signals.

Keywords: Behaviour; Ganglioside; Inflammation; Mucopolysaccharidosis IIIA; N-butyldeoxynojirimycin; Substrate deprivation therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Deoxynojirimycin / analogs & derivatives*
  • 1-Deoxynojirimycin / pharmacology
  • 1-Deoxynojirimycin / therapeutic use
  • Analysis of Variance
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Chemokine CCL3 / metabolism
  • Disease Models, Animal
  • Fear / drug effects
  • Gangliosides / metabolism
  • Glucosyltransferases / antagonists & inhibitors
  • Glucosyltransferases / metabolism
  • Glycoside Hydrolase Inhibitors / pharmacology
  • Glycoside Hydrolase Inhibitors / therapeutic use*
  • Interleukin-1beta / metabolism
  • Maze Learning / drug effects
  • Mice
  • Mucopolysaccharidosis III / drug therapy*
  • Mucopolysaccharidosis III / metabolism
  • Mucopolysaccharidosis III / psychology


  • Ccl3 protein, mouse
  • Chemokine CCL3
  • Gangliosides
  • Glycoside Hydrolase Inhibitors
  • IL1B protein, mouse
  • Interleukin-1beta
  • 1-Deoxynojirimycin
  • miglustat
  • Glucosyltransferases
  • ceramide glucosyltransferase