Neuropathology of mice with targeted disruption of Hexa gene, a model of Tay-Sachs disease.

A murine model of Tay-Sachs disease, the prototype of the GM2 gangliosidoses, was produced through the targeted disruption of the Hexa gene encoding the subunit of alpha-hexosaminidase A. The mice were completely devoid of beta-hexosaminidase A activity and accumulated GM2 ganglioside in the CNS in an age-dependent manner. Neurons with membranous cytoplasmic bodies (MCBs), identical to those described in Tay-Sachs disease, were identified in the brain of these mice. The neurons with MCBs were periodic acid-Schiff-positive on frozen sections and immunostained with anti-GM2 ganglioside antibody. However, unlike Tay-Sachs disease in which neurons throughout the brain are affected, the localization of storage neurons in these mice appeared to be limited to certain regions, i.e., cerebral cortex, the hippocampus, amygdala, hypothalamus, mammillary nucleus, etc. Storage neurons were absent in the olfactory bulb, cerebellar cortex and spinal anterior horns. The difference in the distribution of storage neurons suggests a difference of ganglioside metabolism between humans and mice. This model is useful for the study of the pathogenic mechanisms of neuronal storage in Tay-Sachs disease and for the evaluation of therapeutic strategies.