Specificity of mouse GM2 activator protein and β-N-acetylhexosaminidases A and B -: Similarities and differences with their human counterparts in the catabolism of GM2

Tay Sachs disease, an inborn lysosomal disease featuring a buildup of G(M2) in the brain, is caused by a deficiency of beta-hexosaminidase A (Hex A) or G(M2) activator. Of the two human lysosomal Hex isozymes, only Hex A, not Hex B, cleaves G(M2) in the presence of G(M2) activator. In contrast, mouse Hex B has been reported to be more active than Hex A in cleaving G(M2) (Burg, J., Banerjee, A., Conzelmann, E., and Sandhoff, K. (1983) Hoppe Seyler's Z. Physiol. Chem. 364, 821-829), In two independent studies, mice with the targeted disruption of the Hexa gene did not display the severe buildup of brain G(M2) or the concomitant abnormal behavioral manifestations seen in human Tay-Sachs patients. The results of these two studies were suggested to be attributed to the reported G(M2) degrading activity of mouse Hex B. To clarify the specificity of mouse Hex A and Hex B and to better understand the observed results of the mouse model of Tay-Sachs disease, we have purified mouse liver Hex A and Hex B and also prepared the recombinant mouse G(M2) activator, Contrary to the findings of Burg et al., we found that the specificities of mouse Hex A and Hex B toward the catabolism of G(M2) were not different from the corresponding human Hex isozymes. Mouse Hex A, but not Hex B, hydrolyzes G(M2) in the presence of G(M2) activator, whereas G(M2) is refractory to mouse Hex B with or without G(M2) activator. Importantly, we found that, in contrast to human G(M2) activator, mouse G(M2) activator could effectively stimulate the hydrolysis of G(A2) by mouse Hex A and to a much lesser extent also by Hex B. These results provide clear evidence on the existence of an alternative pathway for G(M2) catabolism in mice by converting G(M2) to G(A2) and subsequently to lactosylceramide. They also provide the explanation for the lack of excessive G(M2) accumulation in the Hexa gene-disrupted mice.