Abstract
In postmortem Huntington's disease brains, mutant htt is present in both nuclear and cytoplasmic compartments. To dissect the impact of nuclear and extranuclear mutant htt on the initiation and progression of disease, we generated a series of transgenic mouse lines in which nuclear localization or nuclear export signal sequences have been placed N-terminal to the htt exon 1 protein carrying 144 glutamines. Our data indicate that the exon 1 mutant protein is present in the nucleus as part of an oligomeric or aggregation complex. Increasing the concentration of the mutant transprotein in the nucleus is sufficient for and dramatically accelerates the onset and progression of behavioral phenotypes. Furthermore, nuclear exon 1 mutant protein is sufficient to induce cytoplasmic neurodegeneration and transcriptional dysregulation. However, our data suggest that cytoplasmic mutant exon 1 htt, if present, contributes to disease progression.
Publication types
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Research Support, N.I.H., Extramural
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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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Animals
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Brain / metabolism
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Brain / pathology
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Brain / ultrastructure
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Cell Nucleus / metabolism*
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Cytoplasm / metabolism
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Disease Models, Animal*
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Gene Expression Profiling
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Gene Expression Regulation
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Humans
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Huntingtin Protein
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Huntington Disease / metabolism*
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Huntington Disease / pathology*
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Macromolecular Substances
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Mice
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Mice, Transgenic
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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 Localization Signals
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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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Peptides / metabolism*
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Phenotype
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rotarod Performance Test
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Transcription, Genetic
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Transgenes / 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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Macromolecular Substances
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Nerve Tissue Proteins
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Nuclear Localization Signals
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Nuclear Proteins
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Peptides
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RNA, Messenger
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polyglutamine