Calmodulin regulates transglutaminase 2 cross-linking of Huntingtin
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Issue Date
2004-02-25Author
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
Metadata
Show full item recordAbstract
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.
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This is the publisher's version, also available electronically from "www.jneurosci.org".
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- Pharmacy Scholarly Works [293]
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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