Abstracts Biological Sciences

The role of mouse and human lysosomal sialidase in the catabolism of ganglioside GM2

by Chris. Gafuik

Tay-Sachs and Sandhoff diseases are autosomal recessive disorders of GM2 ganglioside catabolism resulting from deficient activity of lysosomal beta-hexosaminidase A (Hex A) or Hex A and Hex B, respectively. This leads to a massive and fatal accumulation of GM2 ganglioside in the neurons of affected patients. Mouse models of Tay-Sachs and Sandhoff diseases, created via targeted disruption of the Hexa and Hexb genes, revealed that while Hexb -/- mice suffer a profound, fatal neurodegenerative disease as expected, Hexa -/- mice escape disease to about one year. This protection is conferred by an ability to degrade GM2 ganglioside by means of a lysosomal sialidase mediated metabolic bypass. To determine if such a bypass could be made to function in humans, a series of experiments were performed to examine and compare the activity of mouse and human lysosomal sialidases in their ability to promote GM2 catabolism. The results suggest that human lysosomal sialidase, though sluggish, can indeed degrade GM2 when induced sufficiently.