Abstract
Nine neurodegenerative disorders are caused by CAG/polyglutamine (polyQ) repeat expansions. The molecular mechanisms responsible for disease-specific neurodegeneration remain elusive. We developed an embryonic stem (ES) cell-based model to probe the role of polyQ tract expansion in neuronal degeneration. ES cells containing expanded CAG repeats in the hypoxanthine phosphoribosyltransferase (Hprt) gene develop features typical of CAG-mediated neuropathology, exhibit length-dependent decrease in survival, undergo aberrant neuronal differentiation as well as persistent Oct-4 and Repressor element-1 transcription factor/neuron restrictive silencer factor (REST/NRSF) expression. This novel model will allow analysis of the molecular pathogenesis of neuronal degeneration and can be used to rapidly screen therapeutic interventions for these fatal diseases.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Cell Differentiation / genetics*
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Cell Survival / genetics
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Cells, Cultured
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Heredodegenerative Disorders, Nervous System / genetics
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Heredodegenerative Disorders, Nervous System / metabolism
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Heredodegenerative Disorders, Nervous System / physiopathology
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Humans
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Hypoxanthine Phosphoribosyltransferase / genetics
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Models, Biological
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Neurons / metabolism*
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Neurons / pathology
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Octamer Transcription Factor-3
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Peptides / genetics
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Peptides / metabolism
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Pluripotent Stem Cells / cytology
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Pluripotent Stem Cells / metabolism*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Trinucleotide Repeat Expansion / genetics*
Substances
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DNA-Binding Proteins
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Octamer Transcription Factor-3
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POU5F1 protein, human
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Peptides
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RE1-silencing transcription factor
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Repressor Proteins
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Transcription Factors
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polyglutamine
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Hypoxanthine Phosphoribosyltransferase