Abstract
Bcl-2-associated athanogene-1 (BAG1) is a multifunctional protein delivering chaperone-recognized unfolded substrates to the proteasome for degradation. It has been shown to be essential for proper CNS development in vivo, playing a crucial role in neuronal survival and differentiation. With regard to Huntington's disease, a sequestration of BAG1 into inclusion bodies and a neuroprotective effect in double transgenic mice have been reported. Here, we show that BAG1 reduces aggregation and accelerates degradation of mutant huntingtin (htt-mut). Moreover, it reduces nuclear levels of htt-mut. This effect can be overcome by over-expression of seven in absentia homolog 1, an E3 ligase negatively regulated by BAG1 and known to be involved in nuclear import of htt-mut. In vivo, BAG1 proved to be protective in a Drosophila melanogaster Huntington's disease model, preventing photoreceptor cell loss induced by htt-mut. In summary, we present BAG1 as a therapeutic tool modulating key steps in htt toxicity in vitro and ameliorating htt toxicity in vivo.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Genetically Modified
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Cysteine Proteinase Inhibitors / pharmacology
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Disease Models, Animal
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Drosophila melanogaster
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Green Fluorescent Proteins / genetics
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Humans
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Huntingtin Protein
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Huntington Disease / genetics
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Huntington Disease / metabolism*
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Huntington Disease / pathology*
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Leupeptins / pharmacology
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Mice
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Mutation
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Photoreceptor Cells / metabolism
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Photoreceptor Cells / pathology
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Proteins / metabolism
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Subcellular Fractions / drug effects
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Subcellular Fractions / metabolism*
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Subcellular Fractions / pathology
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Ubiquitin-Protein Ligases
Substances
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BCL2-associated athanogene 1 protein
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Cysteine Proteinase Inhibitors
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DNA-Binding Proteins
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HTT protein, human
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Huntingtin Protein
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Leupeptins
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Nerve Tissue Proteins
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Nuclear Proteins
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Proteins
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Transcription Factors
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enhanced green fluorescent protein
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Green Fluorescent Proteins
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Siah1a protein, mouse
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Ubiquitin-Protein Ligases
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde