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-Sac hs disease, and Sandhoff disease are the major forms of the G(M2) gang liosidoses, disorders caused by defective degradation of G(M2) ganglio side. Tay-Sachs and Sandhoff diseases are caused by mutations in the g enes (HEXA and HEXB) encoding the subunits of beta-hexosaminidase A. T he G(M2) activator deficiency is caused by mutations in the GM2A gene encoding the G(M2) activator protein, For degradation of G(M2) ganglio side by beta-hexosamindase A, the G(M2) activator protein must partici pate by forming a soluble complex with the ganglioside, In each of the disorders, G(M2) ganglioside and related lipids accumulate to patholo gic levels in neuronal lysosomes, resulting in clinically similar diso rders with an onset in the first year of life, progressive neurodegene ration, and death by early childhood, We previously have described mou se models of Tay-Sachs (Hexa -/-) and Sandhoff (Hexb -/-) diseases wit h vastly different clinical phenotypes. The Hexa -/- mice were asympto matic whereas the Hexb -/- mice were severely affected. Through gene d isruption in embryonic stem cells we now have established a mouse mode l of the G(M2) activator deficiency that manifests an intermediate phe notype. The Gm2a -/- mice demonstrated neuronal storage but only in re stricted regions of the brain (piriform, entorhinal cortex, amygdala, and hypothalamic nuclei) reminiscent of the asymptomatic Tay-Sachs mod el mice, However, unlike the Tay-Sachs mice, the Gm2a -/- mice display ed significant storage in the cerebellum and defects in balance and co ordination, The abnormal ganglioside storage in the Gm2a -/- mice cons isted of G(M2) with a low amount of G(A2). The results demonstrate tha t the activator protein is required for G(M2) degradation and also may indicate a role for the G(M2) activator in G(A2) degradation.