Apoptotic Cell Death in Mouse Models of GM2 Gangliosidosis and Observations on Human Tay-Sachs and Sandhoff Diseases

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Abstract
Tay-Sachs and Sandhoff diseases are autosomal recessive neurodegenerative diseases resulting from the inability to catabolize GM2 ganglioside by β-hexos-aminidase A (Hex A) due to mutations of the α subunit (Tay-Sachs disease) or β subunit (Sandhoff disease) of Hex A. Hex B ( ββ homodimer) is also defective in Sandhoff disease. We previously developed 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 apoptosis occurring throughout the CNS, while Hexa−/−mice were minimally involved at the same age. Studies of autopsy samples of brain and spinal cord from human Tay-Sachs and Sandhoff diseases revealed apoptosis in both instances, in keeping with the severe expression of both diseases. We suggest that neuron death is caused by unscheduled apoptosis, implicating accumulated GM2 ganglioside or a derivative in triggering of the apoptotic cascade.