Characterization of a C57BL/6 congenic mouse strain of mucopolysaccharidosis type IIIA.

Abstract

The original mucopolysaccharidosis type IIIA (MPS IIIA) mice were identified in a mixed background with contributions from four different strains. To ensure long-term stability and genetic homogeneity of this lysosomal storage disease (LSD) model, the aim of this study was to develop and characterize a C57BL/6 congenic strain. The B6.Cg-Sgsh(mps3a) strain compares favorably with the original mixed donor strain, exhibiting low liver sulfamidase activity and significant brain heparan sulfate-derived disaccharide elevation from birth. A rapid increase in brain disaccharide levels occurred after birth, with a plateau reached by 13 weeks of age at 110x the levels observed in brains of age-matched unaffected mice. Typical lysosomal inclusions were observed in cerebral cortical and cerebellar neurons and in liver hepatocytes and Kupffer cells. Ubiquitin-positive spheroids and GM(2)-ganglioside were also detected in brain. Using the Morris water maze in male mice, impaired memory and spatial learning was evident at 20 weeks of age in B6.Cg-Sgsh(mps3a) MPS IIIA mice. Other behavioral changes include motor, cognitive and sensory deficits, and aggression. Male B6.Cg-Sgsh(mps3a) MPS IIIA mice exhibited more behavioral abnormalities than B6.Cg-Sgsh(mps3a) MPS IIIA females, as observed previously in the original mixed background strain. Affected mice generally survive to 9 to 12 months of age, before death or euthanasia for humane reasons. Overall, minor differences were apparent between the new congenic and previously described mixed MPS IIIA strains. Availability of an in-bred strain will ensure more reproducible experimental outcomes thereby assisting in our goal of developing effective therapies for LSD with central nervous system disease.

• Authors: Allison C Crawley, Briony L Gliddon, Dyane Auclair, Suzanne L Brodie, Craig Hirte, Barbara M King, Maria Fuller, Kim M Hemsley, John J Hopwood
• Journal: Brain research (Brain Res) Vol. 1104 Issue 1 Pg. 1-17 (Aug 09 2006) ISSN: 0006-8993 [Print] Netherlands
• PMID: 16828069 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ubiquitin
• G(M2) Ganglioside
• Hydrolases
• N-sulfoglucosamine sulfohydrolase

Topics

• Age Factors
• Animals
• Behavior, Animal
• Body Weight (physiology)
• Brain (metabolism, pathology, ultrastructure)
• Breeding (methods)
• Disease Models, Animal
• Exploratory Behavior (physiology)
• Female
• G(M2) Ganglioside (metabolism)
• Gas Chromatography-Mass Spectrometry (methods)
• Hydrolases (deficiency)
• Immunohistochemistry (methods)
• Male
• Maze Learning (physiology)
• Mice
• Mice, Congenic
• Mice, Inbred C57BL
• Microscopy, Electron, Transmission (methods)
• Mucopolysaccharidosis III (genetics, pathology, physiopathology)
• Sex Factors
• Ubiquitin (metabolism)