title: 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.affiliation: Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom. tjs62@cam.ac.uk
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Sargeant
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Drage
authors.forename: Susan
authors.initials: S
authors.lastname: Wang
authors.forename: Apostolos A
authors.initials: AA
authors.lastname: Apostolakis
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Cox
authors.forename: M Begoña
authors.initials: MB
authors.lastname: Cachón-González
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D005678:G(M2) Ganglioside / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012497:Sandhoff Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013661:Tay-Sachs Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics / Q000378:metabolism
chemical_list: D005678:G(M2) Ganglioside; D001619:beta-N-Acetylhexosaminidases; D004318:Doxycycline