Monitoring the CNS pathology in aspartylglucosaminuria mice

Aspartylglucosaminuria (AGU) is a recessively inherited lysosomal storage d isorder caused by the deficiency of the aspartylglucosaminidase (AGA) enzym e. The hallmark of AGU is slowly progressing mental retardation but the pro gression of brain pathology has remained uncharacterized in humans. Here we describe the long-term follow-up of mice carrying a targeted AGU-mutation in both alleles. Immunohistochemistry, histology, electron microscopy, quan titative magnetic resonance imaging (MRI) and behavioral studies were carri ed out to evaluate the CNS affection of the disease during development. The lysosomal storage vacuoles of the AGA -/- mice were most evident in centra l brain regions where MRI also revealed signs of brain atrophy similar to t hat seen in the older human patients. By immunohistochemistry and MRI exami nations, a subtle delay of myelination was observed in AGA -/- mice. The li fe span of the AGA -/- mice was not shortened. Similar to the slow clinical course observed in human patients, the AGA -/- mice have behavioral sympto ms that emerge at older age. Thus, the AGU knock-out mice represent an accu rate model for AGU, both histopathologically and phenotypically.