Protective up-regulation of CK2 by mutant huntingtin in cells co-expressing NMDA receptors |
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Authors: | Fan Mannie M Y Zhang Hong Hayden Michael R Pelech Steven L Raymond Lynn A |
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Institution: | Graduate Program in Neuroscience, University of British Columbia, British Columbia, Canada; Kinexus Bioinformatics Corporation, University of British Columbia, British Columbia, Canada; Centre for Molecular Medicine and Therapeutics, University of British Columbia, British Columbia, Canada; Department of Medical Genetics, University of British Columbia, British Columbia, Canada; Brain Research Centre, University of British Columbia, British Columbia, Canada; Department of Medicine, University of British Columbia, British Columbia, Canada;Department of Psychiatry, University of British Columbia, British Columbia, Canada |
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Abstract: | Huntington's disease is caused by a polyglutamine expansion in the huntingtin (htt) protein, and previous data indicate that over-activation of NMDA receptors (NMDARs) may be involved in the selective degeneration of cells expressing NR1/NR2B NMDARs. We used Kinetworks™ multi-immunoblotting screens to examine expression of 76 protein kinases, 18 protein phosphatases, 25 heat shock/stress proteins, and 27 apoptosis proteins in human embryonic kidney 293 cells transfected with NR1/NR2B and htt containing 15 (htt-15Q; wild-type) or 138 (htt-138Q; mutant) glutamine repeats. Follow-up experiments revealed several proteins involved in the heat-shock response pathway to be up-regulated in the soluble fraction from cells expressing htt-138Q, including protein phosphatase 5 and cyclin-dependent kinase 5. Increased expression in the soluble fraction of htt-138Q-expressing cells was also noted for the stress- and calcium-activated protein-serine/threonine kinase casein kinase 2, a change which was confirmed in striatal tissue of yeast artificial chromosome transgenic mice expressing full-length mutant htt. Inhibition of casein kinase 2 activity in cultured striatal neurons from these mice significantly exacerbated NMDAR-mediated toxicity, as assessed by labeling of apoptotic nuclei. Our findings are consistent with up-regulation of components of the stress response pathway in the presence of polyglutamine-expanded htt and NR1/NR2B which may reflect an attempt at the cellular level to ameliorate the detrimental effects of mutant htt expression. |
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Keywords: | huntingtin Huntington's disease NMDA receptors protein expression profiling |
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