Development of neuropathology in murine MPS IIIA and MPS VII and the effect of N-butyldeoxynojirimycin treatment on MPS IIIA mice.

Abstract

The mucopolysaccharidoses (MPSs) are a family of heritable diseases caused by deficiencies in glycosaminoglycan (GAG) degrading lysosomal enzymes. GAGs accumulate in a range of tissues, resulting in diverse pathology that includes brain degeneration. The secondary accumulation of glycosphingolipids, specifically Gм₂ and Gм₃ gangliosides, occurs in the MPS brain. In MPS IIIA and MPS VII mouse models GAGs and gangliosides began to accumulate prior to the onset of behavioural changes. Gм₂ levels began to rise early, following the trend of GAG accumulation, and increased to 548% and 219% of normal levels in MPS IIIA and MPS VII respectively. Gм₃ levels began to rise later, reaching a peak of 484% and 313% of normal in MPS IIIA and MPS VII respectively. Given that brain Gм₂ and Gм₃ accumulation precedes behavioural deficits, it is possible that these gangliosides contribute to brain degeneration. Thus, gangliosides may be a target for the treatment of MPS brain disease. N-butyldeoxynojirimycin (NB-DNJ) is an iminosugar capable of crossing the blood brain barrier and reducing brain ganglioside synthesis, consequently deceasing overall brain Gм₂ and Gм₃ levels. NB-DNJ treatment of MPS IIIA mice decreased brain Gм₂ and Gм₃ levels in the short but not in the long term. Despite this, the innate fear response was restored and learning ability was equivalent to normal with both lengths of treatment. MPS IIIA mice treated with NB-DNJ also had a reduction in cytokine gene expression, astroglial activation and oxidation of inflammatory lipids. Whether MPS IIIA behavioural improvements were due to a delay in ganglioside accumulation with NB-DNJ treatment, or due to an anti-inflammatory function of NB-DNJ is not known. However, this thesis demonstrates that NB-DNJ can improve MPS brain dysfunction in the MPS IIIA mouse model and may be a potential therapy for CNS disease for children with MPS.