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

PLoS genetics | Sep 2, 2012

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 RIS Download

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

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Cold Spring Harbor Laboratory

A non-profit, private research and education institution that performs molecular and genetic research used to generate methods for better diagnostics and treatments for cancer and neurological diseases. This lab has done specific research of cancer-causing genes and their respective signaling pathways. They have also researched mutations and structural variations of the human genome that could cause neurodevelopmental and neurodegenerative illnesses such as autism, schizophrenia, and Alzheimer's and Parkinson's diseases. This laboratory is also involved in plant genetics and quantitative biology.

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