Tay-Sachs and Sandhoff diseases are lethal inborn errors of
acid β-N-acetylhexosaminidase activity, characterized by lysosomal storage of
GM2 ganglioside and related
glycoconjugates in the nervous system. The molecular events that lead to irreversible neuronal injury accompanied by
gliosis are unknown; but gene transfer, when undertaken before neurological signs are manifest, effectively rescues the acute neurodegenerative illness in Hexb-/- (Sandhoff) mice that lack β-
hexosaminidases A and B. To define determinants of therapeutic efficacy and establish a dynamic experimental platform to systematically investigate cellular pathogenesis of
GM2 gangliosidosis, we generated two inducible experimental models. Reversible transgenic expression of β-
hexosaminidase directed by two promoters, mouse Hexb and human
Synapsin 1 promoters, permitted progression of
GM2 gangliosidosis in Sandhoff mice to be modified at pre-defined ages. A single auto-regulatory
tetracycline-sensitive expression cassette controlled expression of transgenic Hexb in the brain of Hexb-/- mice and provided long-term rescue from the acute neuronopathic disorder, as well as the accompanying pathological storage of
glycoconjugates and
gliosis in most parts of the brain. Ultimately, late-onset brainstem and ventral spinal cord pathology occurred and was associated with increased tone in the limbs. Silencing transgenic Hexb expression in five-week-old mice induced stereotypic signs and progression of
Sandhoff disease, including
tremor,
bradykinesia, and hind-limb
paralysis. As in germline Hexb-/- mice, these neurodegenerative manifestations advanced rapidly, indicating that the pathogenesis and progression of
GM2 gangliosidosis is not influenced by developmental events in the maturing nervous system.