Abstract
Proteolytic processing of mutant huntingtin (mhtt) is regarded as a key event in the pathogenesis of Huntington's disease (HD). Mhtt fragments containing a polyglutamine expansion form intracellular inclusions and are more cytotoxic than full-length mhtt. Here, we report that two distinct mhtt fragments, termed cp-A and cp-B, differentially build up nuclear and cytoplasmic inclusions in HD brain and in a cellular model for HD. Cp-A is released by cleavage of htt in a 10 amino acid domain and is the major fragment that aggregates in the nucleus. Furthermore, we provide evidence that cp-A and cp-B are most likely generated by aspartic endopeptidases acting in concert with the proteasome to ensure the normal turnover of htt. These proteolytic processes are thus potential targets for therapeutic intervention in HD.
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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Amino Acid Sequence
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Brain / metabolism
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Brain / pathology
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Cell Line
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Cell Nucleus / metabolism*
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Cytoplasm / metabolism*
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Endopeptidases / metabolism*
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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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Immunohistochemistry
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Inclusion Bodies / metabolism
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Models, Biological
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Molecular Sequence Data
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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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Nuclear Proteins / chemistry
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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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 Processing, Post-Translational
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Protein Structure, Tertiary
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Substrate Specificity
Substances
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HTT protein, human
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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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Endopeptidases