Apoptotic cell death in mouse models of GM2 gangliosidosis and observations on human Tay-Sachs and Sandhoff diseases

Tay-Sachs and Sandhoff diseases are autosomal recessive neurodegenerativediseases resulting from the inability to catabolize GM2 ganglioside bybeta-hexosaminidase A (Hex A) due to mutations of the alpha subunit(Tay-Sachs disease) or beta subunit (Sandhoff disease) of Hex A. Hex B(beta beta homodimer) is also defective in Sandhoff disease. We previouslydeveloped mouse models of both diseases and showed that Hexa-/- (Tay-Sachs)mice remain asymptomatic to at least 1 year of age while Hexb-/- (Sandhoff)mice succumb to a profound neurodegenerative disease by 4-6 months of age.Here we find that neuron death in Hexb-/- mice is associated with apoptosisoccurring throughout the CNS, while Hexa-/- mice were minimally involved atthe same age. Studies of autopsy samples of brain and spinal cord fromhuman Tay-Sachs and Sandhoff diseases revealed apoptosis in both instances,in keeping with the severe expression of both diseases. We suggest thatneuron death is caused by unscheduled apoptosis, implicating accumulatedGM2 ganglioside or a derivative in triggering of the apoptotic cascade.