Abstract
Huntington's disease (HD) is a neurodegenerative disease caused by polyglutamine (polyQ) expansion in the protein huntingtin (htt). Pathogenesis in HD seems to involve the formation of neuronal intranuclear inclusions and the abnormal regulation of transcription and signal transduction. To identify previously uncharacterized htt-interacting proteins in a simple model system, we used a yeast two-hybrid screen with a Caenorhabditis elegans activation domain library. We found a predicted SH3 domain protein (K08E3.3b) that interacts with N-terminal htt in two-hybrid tests. A human homolog of K08E3.3b is the Cdc42-interacting protein 4 (CIP4), a protein involved in Cdc42 and Wiskott-Aldrich syndrome protein-dependent signal transduction. CIP4 interacted in vitro with full-length htt from lymphoblastoid cells. Neuronal CIP4 immunoreactivity increased with neuropathological severity in the neostriatum of HD patients and partially colocalized to ubiquitin-positive aggregates. Marked CIP4 overexpression also was observed in Western blot from human HD brain striatum. The overexpression of CIP4 induced the death of striatal neurons. Our data suggest that CIP4 accumulation and cellular toxicity may have a role in HD pathogenesis.
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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Aged
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Animals
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Blotting, Western
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Brain / cytology
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Brain / metabolism
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Caenorhabditis elegans / metabolism
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Cell Death
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Cells, Cultured
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Electrophoresis, Polyacrylamide Gel
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Gene Library
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Humans
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Huntingtin Protein
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Huntington Disease / genetics*
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Huntington Disease / pathology*
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Immunohistochemistry
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Lymphocytes / metabolism
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Microtubule-Associated Proteins / metabolism*
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Microtubule-Associated Proteins / physiology*
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Middle Aged
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Minor Histocompatibility Antigens
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Mutation
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Nerve Tissue Proteins / chemistry*
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Nerve Tissue Proteins / metabolism
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Neurons / cytology
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Neurons / pathology
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Nuclear Proteins / chemistry*
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Nuclear Proteins / metabolism
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Peptides / chemistry
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Protein Binding
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Protein Structure, Tertiary
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RNA, Messenger / metabolism
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Rats
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Rats, Sprague-Dawley
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Signal Transduction
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Time Factors
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Two-Hybrid System Techniques
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Ubiquitin / metabolism
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Up-Regulation
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rho GTP-Binding Proteins / metabolism
Substances
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HTT protein, human
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Htt protein, rat
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Huntingtin Protein
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Microtubule-Associated Proteins
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Minor Histocompatibility Antigens
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Nerve Tissue Proteins
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Nuclear Proteins
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Peptides
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RNA, Messenger
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TRIP10 protein, human
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Trip10 protein, rat
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Ubiquitin
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polyglutamine
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rho GTP-Binding Proteins