Toward understanding the neuronal pathogenesis of aspartylglucosaminuria: Expression of aspartylglucosaminidase in brain during development

The deficiency of a lysosomal enzyme, aspartylglucosaminidase, results in a lysosomal storage disorder, aspartylglucosaminuria, manifesting as progres sive mental retardation. To understand tissue pathogenesis and disease prog ression we analyzed the developmental expression of the enzyme, especially in brain, which is the major source of the pathological symptoms. Highest m RNA levels in brain were detected during embryogenesis, the levels decrease d neonatally and started to increase again from Day 7 on. In Western analys es, a defective processing of aspartylglucosaminidase was observed in brain as compared to other tissues, resulting in very low levels of the mature, active form of the enzyme. Interestingly immunohistochemical analyses of mo use brain revealed that aspartylglucosaminidase immunoreactivity closely mi micked the myelin basic protein immunostaining pattern. The only evident ne uronal staining was observed in the developing Purkinje cells of the cerebe llum from Days 3 to 10, reflecting well the mRNA expression. In human infan t brain, the immunostaining was also present in myelinated fibers as well a s in the Purkinje cells and, additionally, in the soma and extensions of ot her neurons. In the adult human brain neurons and oligodendrocytes displaye d immunoreactivity whereas myelinated fibers were not stained. Our results of aspartylglucosaminidase immunostaining in myelinated fibers of infant br ain might imply the involvement of aspartylglucosaminidase in the early mye lination process. This is consistent with previous magnetic resonance imagi ng findings in the brains of aspartylglucosaminuria patients, revealing del ayed myelination in childhood. (C) 1999 Academic Press.