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The Journal of Neuroscience, February 25, 2004, 24(8):1954-1961; doi:10.1523/JNEUROSCI.4424-03.2004

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Neurobiology of Disease
Calmodulin Regulates Transglutaminase 2 Cross-Linking of Huntingtin

Gina M. Zainelli,¹ Christopher A. Ross,³ Juan C. Troncoso,⁴ John K. Fitzgerald,² and Nancy A. Muma¹

Departments of ¹Pharmacology and ²Cell Biology, Neurobiology, and Anatomy, Loyola University Medical Center, Maywood, Illinois 60153, and Departments of ³Psychiatry, Neurology, and Neuroscience and ⁴Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

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.

Key words: calmodulin; Huntington; transglutaminase; protein aggregation; inclusion bodies; cross-linking

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Received Sep 30, 2003; revised December 16, 2003; accepted December 17, 2003.

This article has been cited by other articles:

				Y. Dai, N. L. Dudek, Q. Li, S. C. Fowler, and N. A. Muma Striatal Expression of a Calmodulin Fragment Improved Motor Function, Weight Loss, and Neuropathology in the R6/2 Mouse Model of Huntington's Disease J. Neurosci., September 16, 2009; 29(37): 11550 - 11559. [Abstract] [Full Text] [PDF]

				S. V. Rakhilin, P. A. Olson, A. Nishi, N. N. Starkova, A. A. Fienberg, A. C. Nairn, D. J. Surmeier, and P. Greengard A Network of Control Mediated by Regulator of Calcium/Calmodulin-Dependent Signaling Science, October 22, 2004; 306(5696): 698 - 701. [Abstract] [Full Text] [PDF]

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