Abstract
The cause of Huntington disease pathophysiology is unknown, but a major hypothesis suggests that toxicity arises from the cleavage and accumulation of amino-terminal fragments containing an expanded polyglutamine region. In evaluating huntingtin protein (HD) from human brain, transgenic animals and cells, we observed, unexpectedly, that mutant HD is more resistant to proteolysis than normal HD. The N-terminal cleavage fragments we observed arise from the processing of normal HD and are sequestered by full-length mutant HD. Our results support a model in which inhibition of proteolysis of mutant HD leads to aggregation and toxicity through the sequestering of important targets, including normal HD.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Aged
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Animals
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Brain / metabolism*
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Brain / pathology
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Caspase 3
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Caspases / metabolism
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Cell Death
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Cell Line
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Chromatography, Gel
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Female
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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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Huntington Disease / physiopathology
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Male
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Mice
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Middle Aged
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Models, Biological
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Mutation / genetics*
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Nerve Tissue Proteins / chemistry
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Nerve Tissue Proteins / genetics*
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Nerve Tissue Proteins / metabolism*
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Nerve Tissue Proteins / toxicity
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Nuclear Proteins / chemistry
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism*
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Nuclear Proteins / toxicity
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Organ Specificity
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Peptide Fragments / chemistry
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Peptide Fragments / metabolism
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Protein Binding
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Protein Structure, Quaternary
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Solubility
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Trinucleotide Repeat Expansion / genetics
Substances
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HTT protein, human
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Htt protein, mouse
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Huntingtin Protein
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Nerve Tissue Proteins
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Nuclear Proteins
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Peptide Fragments
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CASP3 protein, human
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Casp3 protein, mouse
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Caspase 3
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Caspases