18. Targeting the hexosaminidase genes: Mouse models of the GM2 gangliosidoses

Abstract

Publisher Summary This chapter deals with the study of mouse models of the G M2 gangliosidoses. The onset of neurological symptoms in Tay-Sachs disease patients normally occurs by 3 to 5 months after birth. As a result of their β-hexosaminidase A deficiency, G M2 ganglioside accumulated in the brains of the Tay-Sachs mice in an age-dependent fashion. This G M2 ganglioside accumulation resulted in storage neurons with membranous cytoplasmic bodies (MCBs) that were identical to affected neurons in Tay-Sachs disease patients. In human cells, β -hexosaminidase A degrades G M2 ganglioside to form G M3 . In addition to this pathway, mouse cells also have a detour pathway where G M2 is converted to G A2 by the action of sialidase. G A2 can now be further degraded by β-hexosaminidase B (or A) and then by the action of other glycosidases to yield ceramide. In the Tay-Sachs mice the G M2 to G M3 conversion is blocked because of the absence of β-hexosaminidase A. Each of the human mucopolysaccharidoses involves the heritable absence of one of the enzymes that are required for the lysosomal degradation of glycosaminoglycans. The lack of a mucopolysaccharidosis phenotype in humans and mice with one β-hexosaminidase gene mutated is, therefore, due to functional redundancy in the enzyme system.