Molecular pathology of mucopolysaccaridosis IIIB

Mucopolysaccharidosis IIIB (MPS IIIB, Sanfilippo syndrome type B) is caused by a deficiency of the lysosomal enzyme alpha-N-acetylglucosaminidase. The disease is characterized, clinically, by profound neurological deterioration but relatively mild somatic manifestations. The pathogenetic bases of the neurological disease remain obscure; however, a murine model of the MPS IIIB disease is available and suitable both for therapeutic approaches and pathogenesis studies. A first report on the reduction of brain function in this model showed important alterations in the maintenance of neuroplasticity, associated to drastic induction of reactive astrocytes (1). A subsequent study on brain cortex highlighted the involvement of microglia and neuroinflammation in the brain pathology (2). We hypothesized that a pathway focused quantitative analysis of gene expression in the whole brain and in cerebellum of MPS IIIB affected mice, performed at several times from birth (1, 3 and 7 months) would contribute to better illuminate the molecular mechanisms underlying the neuropathology in the MPS IIIB disease. Therefore, we used filter microarrays designed to probe apoptotic-related, neurotrophic signaling molecules, and inflammatory cytokines and receptors. Moreover, we extended the analysis and enhanced the sensitivity of our approach with reverse transcription real time PCR using several gene-specific primer sets. From these combined analyses the Bdnf gene resulted to be down-regulated in the brain but up-regulated in the cerebellum. Cbln1 presented a 2 fold increase in the brain while resting unaltered in the cerebellum of MPS IIIB mice. All the other analysed genes, namely Ccl3, Casp3, Casp11, gp91phox, p67 and p47, showed an increased expression in both brain and cerebellum at every time from birth; particularly, Ccl3 exhibited in both organs and at all times tested approximately a ten-fold increase of its expression. Interestingly, p47, p67 and gp91phox are all components of the phagocyte NADPH oxidase that catalyzes the superoxide production; these results seem to suggest the possible involvement of the reactive oxygen species in the genesis of neurodegeneration for the MPS IIIB mice. The NADPH oxidase-derived superoxide made by the activated microglia could play an important role in the inflammation-mediated damage to neurons.