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

Abstract

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.

• Authors: Timothy J Sargeant, Deborah J Drage, Susan Wang, Apostolos A Apostolakis, Timothy M Cox, M Begoña Cachón-González
• Journal: PLoS genetics (PLoS Genet) Vol. 8 Issue 9 Pg. e1002943 (Sep 2012) ISSN: 1553-7404 [Electronic] United States
• PMID: 23028353 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• G(M2) Ganglioside
• beta-N-Acetylhexosaminidases
• Doxycycline

Topics

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