NEUROPATHOLOGY OF MICE WITH TARGETED DISRUPTION OF HEXA GENE, A MODELOF TAY-SACHS-DISEASE

A murine model of Tay-Sachs disease, the prototype of the GM(2) gangli osidoses, was produced through the targeted disruption of the Hexa gen e encoding the subunit of alpha-hexosaminidase A. The mice were comple tely devoid of beta-hexosaminidase A activity and accumulated GM(2) ga nglioside in the CNS in an age-dependent manner. Neurons with membrano us cytoplasmic bodies (MCBs), identical to those described in Tay-Sach s disease, were identified in the brain of these mice. The neurons wit h MCBs were periodic acid-Schiff-positive on frozen sections and immun ostained with anti-GM(2) ganglioside antibody. However, unlike Tay-Sac hs disease in which neurons throughout the brain are affected, the loc alization of storage neurons in these mice appeared ts be limited to c ertain regions, i.e., cerebral cortex, the hippocampus, amygdala, hypo thalamus, mammillary nucleus, etc. Storage neurons were absent in the olfactory bulb, cerebellar cortex and spinal anterior hems. The differ ence in the distribution of storage neurons suggests a difference of g anglioside metabolism between humans and mice. This model is useful fo r the study of the pathogenic mechanisms of neuronal storage in Tay-Sa chs disease and for the evaluation of therapeutic strategies.