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    Calmodulin regulates transglutaminase 2 cross-linking of Huntingtin

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    MumaN_JN_24(8)1954.pdf (373.9Kb)
    Issue Date
    2004-02-25
    Author
    Zainelli, Gina M.
    Ross, Christopher A.
    Troncoso, Juan C.
    Fitzgerald, John K.
    Muma, Nancy A.
    Publisher
    Society for Neuroscience
    Type
    Article
    Article Version
    Scholarly/refereed, publisher version
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    Abstract
    Striatal and cortical intranuclear inclusions and cytoplasmic aggregates of mutant huntingtin are prominent neuropathological hallmarks of Huntington's disease (HD). We demonstrated previously that transglutaminase 2 cross-links mutant huntingtin in cells in culture and demonstrated the presence of transglutaminase-catalyzed cross-links in the HD cortex that colocalize with transglutaminase 2 and huntingtin. Because calmodulin regulates transglutaminase activity in erythrocytes, platelets, and the gizzard, we hypothesized that calmodulin increases cross-linking of huntingtin in the HD brain. We found that calmodulin colocalizes at the confocal level with transglutaminase 2 and with huntingtin in HD intranuclear inclusions. Calmodulin coimmunoprecipitates with transglutaminase 2 and huntingtin in cells transfected with myc-tagged N-terminal huntingtin fragments containing 148 polyglutamine repeats (htt-N63-148Q-myc) and transglutaminase 2 but not in cells transfected with myc-tagged N-terminal huntingtin fragments containing 18 polyglutamine repeats. Our previous studies demonstrated that transfection with both htt-N63-148Q-myc and transglutaminase 2 resulted in cross-linking of mutant huntingtin protein fragments and the formation of insoluble high-molecular-weight aggregates of huntingtin protein fragments. Transfection with transglutaminase 2 and htt-N63-148Q-myc followed by treatment of cells with N-(6-aminohexyl)-1-naphthalenesulfonamide, a calmodulin inhibitor, resulted in a decrease in cross-linked huntingtin. Inhibiting the interaction of calmodulin with transglutaminase and huntingtin protein could decrease cross-linking and diminish huntingtin aggregate formation in the HD brain.
    Description
    This is the publisher's version, also available electronically from "www.jneurosci.org".
    URI
    http://hdl.handle.net/1808/17700
    DOI
    https://doi.org/10.1523/JNEUROSCI.4424-03.2004
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    • Pharmacy Scholarly Works [280]
    Citation
    Zainelli, G. M., Ross, C. A., Trsoncoso, J. C., Fitzgerald, J. K. & Muma, N.A. (2004) Calmodulin regulates transglutaminase 2 cross-linking of Huntingtin. The Journal for Neuroscience, 24(8), 1954-1961. http://www.dx.doi.org/10.1523/JNEUROSCI.4424-03.2004

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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