Oxidative damage and cytotoxic cell involvement in the neuronal pathogenesis of mucopolysaccharidosis IIIB

Mucopolysaccharidosis IIIB (MPS IIIB) is a lysosomal storage disease due to mutations in the gene encoding alpha-N-acetylglucosaminidase and is characterized by a severe neurological disorder. Although several studies have been reported for the murine model of the disease, the molecular basis and the sequence of events leading to neurodegeneration remain to be clarified. We previously suggested the possible involvement of the reactive oxygen species, namely the superoxide ion produced by the microglial NADPH oxidase complex, in the disease pathogenesis (Villani et al, 2007). In the present study we extended the analysis of oxidative stress by evaluating the production of superoxide ions throughout the CNS and by evaluating the effect of the stress on the cellular macromolecules. These approaches applied to one-month-old, three-month-old and six-month-old mice revealed that oxidative stress is present in the affected cerebrum and cerebellum tissues from one month from birth, mainly in the rostral region (208 % compared to normal control), and that it results primarily in protein oxidation, with lipid peroxidation, and especially DNA oxidation, appearing milder and restricted essentially to the cerebellum. Our findings show that oxidative stress and all the analyzed stress-related pathological changes occurr very early in the disease course, most likely before one month of age. We also identified additional genes possibly associated with the neuropathology of MPS IIIB disease. Real time RT-PCR analysis revealed an altered expression of the Sod1, Ret, Bmp4, Tgfb, Gzmb and Prf1 genes. Since Gzmb and Prf1 are proteins secreted by NK/cytotoxic T-cells, these data suggest the involvement of cytotoxic cells in the neuronal pathogenesis.