MAPK dysregulation in the brain pathology of mucopolysaccharidosis IIIB disease

The accumulation of heparan sulfate (HS) in lysosomes is the primary consequence of the enzyme defect (?-N-acetylglucosaminidase) in Mucopolysaccharidosis type IIIB. This accumulation triggers a cascade of pathological events that progressively leads to CNS pathology. Here we examined the activation of the three major stress kinases in the neuronal tissue of a murine model of the disease. ERK1/2 was significantly higher in the cortex of 1-2-month-old affected animals compared to wild type (Wt) littermates. Similarly, ERK 1/2 was stimulated in neurons cultured from MPS IIIB mice. SAPK/JNK was also found to be activated in the cortex of 1-2-month-old affected animals compared to Wt subjects, and the same was found for cultured neurons. In contrast, the active form of p38MAPK was lower in the cortex of 1-month-old MPS IIIB mice compared to Wt animals, but no significant difference was found between the two p38MAPK analyzed in normal and affected neurons cultured in vitro. The differential activation of these kinases in the mouse brain at a very early stage of the disease course suggests a selective stress signature imposed by the lysosomal dysfunction.