Interaction of the nuclear matrix protein NAKAP with HypA and huntingtin: Implications for nuclear toxicity in Huntington's disease pathogenesis

Jonathan A. Sayer, Maria Manczak, Lakshmi Akileswaran, P (Hemachandra) Reddy, Vincent M. Coghlan

    Research output: Contribution to journalArticle

    6 Citations (Scopus)

    Abstract

    Although expansion of a polyglutamine tract in the huntingtin protein is known to cause Huntington's disease (HD), there is considerable debate as to how this mutation leads to the selective neuronal loss that characterizes the disease. The observation that mutant huntingtin accumulates in neuronal nuclei has led to the hypothesis that the molecular mechanism may involve the disruption of specific nuclear activities. Recently, several nuclear interaction partners for huntingtin have been identified, including HypA, a splicing factor-like protein of unknown function. Using a yeast two-hybrid screen, we have identified the interaction of HypA with the nuclear scaffold protein NAKAP. Interaction of NAKAP with HypA is specific and occurs both in yeast and in vitro. Deletion-mapping studies indicate that binding occurs via a proline-rich domain in NAKAP with a WW domain of HypA. In cultured cells, NAKAP and HypA localize within the nucleus and copurify with the nuclear matrix. Furthermore, NAKAP associates with HypA from human brain and copurifies with huntingtin protein in brain tissue obtained from HD patients. In HD neurons, NAKAP and mutant huntingtin were colocalized to the nuclear matrix and were found to be components of nuclear aggregates. Hence, the NAKAP-HypA scaffold is a potential nuclear docking site for huntingtin protein and may contribute to the nuclear accumulation of huntingtin observed in HD.

    Original languageEnglish (US)
    Pages (from-to)297-310
    Number of pages14
    JournalNeuroMolecular Medicine
    Volume7
    Issue number4
    DOIs
    StatePublished - Nov 2005

    Fingerprint

    Nuclear Matrix-Associated Proteins
    Huntington Disease
    Nuclear Matrix
    Yeasts
    Brain
    Proline
    Cultured Cells
    Neurons
    Mutation
    Huntingtin Protein
    Proteins

    Keywords

    • Huntingtin
    • Huntington's disease
    • Nuclear aggregates
    • Nuclear matrix
    • Scaffold protein

    ASJC Scopus subject areas

    • Neuroscience(all)
    • Genetics
    • Cell Biology

    Cite this

    Interaction of the nuclear matrix protein NAKAP with HypA and huntingtin : Implications for nuclear toxicity in Huntington's disease pathogenesis. / Sayer, Jonathan A.; Manczak, Maria; Akileswaran, Lakshmi; Reddy, P (Hemachandra); Coghlan, Vincent M.

    In: NeuroMolecular Medicine, Vol. 7, No. 4, 11.2005, p. 297-310.

    Research output: Contribution to journalArticle

    Sayer, Jonathan A. ; Manczak, Maria ; Akileswaran, Lakshmi ; Reddy, P (Hemachandra) ; Coghlan, Vincent M. / Interaction of the nuclear matrix protein NAKAP with HypA and huntingtin : Implications for nuclear toxicity in Huntington's disease pathogenesis. In: NeuroMolecular Medicine. 2005 ; Vol. 7, No. 4. pp. 297-310.
    @article{76be9178288b40828b7b97641b99aeac,
    title = "Interaction of the nuclear matrix protein NAKAP with HypA and huntingtin: Implications for nuclear toxicity in Huntington's disease pathogenesis",
    abstract = "Although expansion of a polyglutamine tract in the huntingtin protein is known to cause Huntington's disease (HD), there is considerable debate as to how this mutation leads to the selective neuronal loss that characterizes the disease. The observation that mutant huntingtin accumulates in neuronal nuclei has led to the hypothesis that the molecular mechanism may involve the disruption of specific nuclear activities. Recently, several nuclear interaction partners for huntingtin have been identified, including HypA, a splicing factor-like protein of unknown function. Using a yeast two-hybrid screen, we have identified the interaction of HypA with the nuclear scaffold protein NAKAP. Interaction of NAKAP with HypA is specific and occurs both in yeast and in vitro. Deletion-mapping studies indicate that binding occurs via a proline-rich domain in NAKAP with a WW domain of HypA. In cultured cells, NAKAP and HypA localize within the nucleus and copurify with the nuclear matrix. Furthermore, NAKAP associates with HypA from human brain and copurifies with huntingtin protein in brain tissue obtained from HD patients. In HD neurons, NAKAP and mutant huntingtin were colocalized to the nuclear matrix and were found to be components of nuclear aggregates. Hence, the NAKAP-HypA scaffold is a potential nuclear docking site for huntingtin protein and may contribute to the nuclear accumulation of huntingtin observed in HD.",
    keywords = "Huntingtin, Huntington's disease, Nuclear aggregates, Nuclear matrix, Scaffold protein",
    author = "Sayer, {Jonathan A.} and Maria Manczak and Lakshmi Akileswaran and Reddy, {P (Hemachandra)} and Coghlan, {Vincent M.}",
    year = "2005",
    month = "11",
    doi = "10.1385/NMM:7:4:297",
    language = "English (US)",
    volume = "7",
    pages = "297--310",
    journal = "NeuroMolecular Medicine",
    issn = "1535-1084",
    publisher = "Humana Press",
    number = "4",

    }

    TY - JOUR

    T1 - Interaction of the nuclear matrix protein NAKAP with HypA and huntingtin

    T2 - Implications for nuclear toxicity in Huntington's disease pathogenesis

    AU - Sayer, Jonathan A.

    AU - Manczak, Maria

    AU - Akileswaran, Lakshmi

    AU - Reddy, P (Hemachandra)

    AU - Coghlan, Vincent M.

    PY - 2005/11

    Y1 - 2005/11

    N2 - Although expansion of a polyglutamine tract in the huntingtin protein is known to cause Huntington's disease (HD), there is considerable debate as to how this mutation leads to the selective neuronal loss that characterizes the disease. The observation that mutant huntingtin accumulates in neuronal nuclei has led to the hypothesis that the molecular mechanism may involve the disruption of specific nuclear activities. Recently, several nuclear interaction partners for huntingtin have been identified, including HypA, a splicing factor-like protein of unknown function. Using a yeast two-hybrid screen, we have identified the interaction of HypA with the nuclear scaffold protein NAKAP. Interaction of NAKAP with HypA is specific and occurs both in yeast and in vitro. Deletion-mapping studies indicate that binding occurs via a proline-rich domain in NAKAP with a WW domain of HypA. In cultured cells, NAKAP and HypA localize within the nucleus and copurify with the nuclear matrix. Furthermore, NAKAP associates with HypA from human brain and copurifies with huntingtin protein in brain tissue obtained from HD patients. In HD neurons, NAKAP and mutant huntingtin were colocalized to the nuclear matrix and were found to be components of nuclear aggregates. Hence, the NAKAP-HypA scaffold is a potential nuclear docking site for huntingtin protein and may contribute to the nuclear accumulation of huntingtin observed in HD.

    AB - Although expansion of a polyglutamine tract in the huntingtin protein is known to cause Huntington's disease (HD), there is considerable debate as to how this mutation leads to the selective neuronal loss that characterizes the disease. The observation that mutant huntingtin accumulates in neuronal nuclei has led to the hypothesis that the molecular mechanism may involve the disruption of specific nuclear activities. Recently, several nuclear interaction partners for huntingtin have been identified, including HypA, a splicing factor-like protein of unknown function. Using a yeast two-hybrid screen, we have identified the interaction of HypA with the nuclear scaffold protein NAKAP. Interaction of NAKAP with HypA is specific and occurs both in yeast and in vitro. Deletion-mapping studies indicate that binding occurs via a proline-rich domain in NAKAP with a WW domain of HypA. In cultured cells, NAKAP and HypA localize within the nucleus and copurify with the nuclear matrix. Furthermore, NAKAP associates with HypA from human brain and copurifies with huntingtin protein in brain tissue obtained from HD patients. In HD neurons, NAKAP and mutant huntingtin were colocalized to the nuclear matrix and were found to be components of nuclear aggregates. Hence, the NAKAP-HypA scaffold is a potential nuclear docking site for huntingtin protein and may contribute to the nuclear accumulation of huntingtin observed in HD.

    KW - Huntingtin

    KW - Huntington's disease

    KW - Nuclear aggregates

    KW - Nuclear matrix

    KW - Scaffold protein

    UR - http://www.scopus.com/inward/record.url?scp=29244464786&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=29244464786&partnerID=8YFLogxK

    U2 - 10.1385/NMM:7:4:297

    DO - 10.1385/NMM:7:4:297

    M3 - Article

    C2 - 16391387

    AN - SCOPUS:29244464786

    VL - 7

    SP - 297

    EP - 310

    JO - NeuroMolecular Medicine

    JF - NeuroMolecular Medicine

    SN - 1535-1084

    IS - 4

    ER -