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

Abstract

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 G(M2) ganglioside in brain, much more so in Hexb -/- mice, and the latter also accumulate glycolipid G(A2). 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 G(M2). We propose that Hexa -/- mice escape disease through partial catabolism of accumulated G(M2) via G(A2) (asialo-G(M2)) through the combined action of sialidase and β-hexosaminidase B.