APOPTOTIC CELL-DEATH IN MOUSE MODELS OF G(M2) GANGLIOSIDOSIS AND OBSERVATIONS ON HUMAN TAY-SACHS AND SANDHOFF-DISEASES

Tay-Sachs and Sandhoff diseases are autosomal recessive neurodegenerat ive diseases resulting from the inability to catabolize G(M2) ganglios ide by beta-hexosaminidase A (Hex A) due to mutations of the alpha sub unit (Tay-Sachs disease) or beta subunit (Sandhoff disease) of Hex A. Hex B (beta beta homodimer) is also defective in Sandhoff disease. We previously developed mouse models of both diseases and showed that Hex a(-/-)(Tay-Sachs) mice remain asymptomatic to at least 1 year of age w hile Hexb(-/-)(Sandhoff) mice succumb to a profound neurodegenerative disease by 4-6 months of age. Here we find that neuron death in Herb(- /-) mice is associated with apoptosis occurring throughout the CNS, wh ile Hexa(-/-) mice were minimally involved at the same age. Studies of autopsy samples of brain and spinal cord from human Tay-Sachs and San dhoff diseases revealed apoptosis in both instances, in keeping with t he severe expression of both diseases. We suggest that neuron death is caused by unscheduled apoptosis, implicating accumulated G(M2) gangli oside or a derivative in triggering of the apoptotic cascade.