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Characterization of inducible models of Tay-Sachs and related disease.

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.

Pubmed ID: 23028353


  • Sargeant TJ
  • Drage DJ
  • Wang S
  • Apostolakis AA
  • Cox TM
  • Cachón-González MB


PLoS genetics

Publication Data

September 2, 2012

Associated Grants

  • Agency: Medical Research Council, Id: MR/K025570/1

Mesh Terms

  • Animals
  • Brain
  • Disease Models, Animal
  • Doxycycline
  • G(M2) Ganglioside
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Lysosomes
  • Mice
  • Mice, Transgenic
  • Neurons
  • Promoter Regions, Genetic
  • Sandhoff Disease
  • Spinal Cord
  • Tay-Sachs Disease
  • beta-N-Acetylhexosaminidases