ARTICLE Dramatically different phenotypes in mouse models of human Tay-Sachs and Sandhoff diseases

We have generated mouse models of human Tay-Sachs and Sandhoff diseases by targeted disruption of the Hexa (α subunit) or Hexb (β subunit) genes, respectively, encoding lysosomal β-hexosaminidase A (structure, α) and B (structure, ββ). Both mutant mice accumulate GM2 ganglioside in brain, much more so in Hexb –/ – mice, and the latter also accumulate glycolipid GA2. Hexa –/ – mice suffer no obvious behavioral or neurological deficit, while Hexb –/ – mice develop a fatal neurodegenerative disease, with spasticity, muscle weakness, rigidity, tremor and ataxia. The Hexb –/ – but not the Hexa –/ – mice have massive depletion of spinal cord axons as an apparent consequence of neuronal storage of GM2. We propose that Hexa –/ – mice escape disease through partial catabolism of accumulated GM2 via GA2 (asialo-GM2) through the combined action of sialidase and β-hexosaminidase B