Mouse model of G(M2) activator deficiency manifests cerebellar pathology and motor impairment

The G(M2) activator deficiency (also known as the AB variant), Tay- Sachs disease, and Sandhoff disease are the major forms of the G(M2) gangliosidoses, disorders caused by defective degradation of G(M2) ganglioside. Tay-Sachs and Sandhoff diseases are caused by mutations in the genes (HEXA and HEXB) encoding the subunits of β-hexosaminidase A. The G(M2) activator deficiency is caused by mutations in the GM2A gene encoding the G(M2) activator protein. For degradation of G(M2) ganglioside by β- hexosamindase A, the G(M2) activator protein must participate by forming a soluble complex with the ganglioside. In each of the disorders, G(M2) ganglioside and related lipids accumulate to pathologic levels in neuronal lysosomes, resulting in clinically similar disorders with an onset in the first year of life, progressive neurodegeneration, and death by early childhood. We previously have described mouse models of Tay-Sachs (Hexa -/-) and Sandhoff (Hexb -/-) diseases with vastly different clinical phenotypes. The Hexa -/- mice were asymptomatic whereas the Hexb -/- mice were severely affected. Through gene disruption in embryonic stem cells we now have established a mouse model of the G(M2) activator deficiency that manifests an intermediate phenotype. The Gm2a -/- mice demonstrated neuronal storage but only in restricted regions of the brain (piriform, entorhinal cortex, amygdala, and hypothalamic nuclei) reminiscent of the asymptomatic Tay-Sachs model mice. However, unlike the Tay-Sachs mice, the Gm2a -/- mice displayed significant storage in the cerebellum and defects in balance and coordination. The abnormal ganglioside storage in the Gm2a -/- mice consisted of G(M2) with a low amount of G(A2). The results demonstrate that the activator protein is required for G(M2) degradation and also may indicate a role for the G(M2) activator in G(A2) degradation.