Protective up-regulation of CK2 by mutant huntingtin in cells co-expressing NMDA receptors.
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 Kinetworkstrade mark 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.
Fan
Mannie M Y
MM
Graduate Program in Neuroscience, University of British Columbia, British Columbia, Canada.
Zhang
Hong
H
Hayden
Michael R
MR
Pelech
Steven L
SL
Raymond
Lynn A
LA
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D047390:Casein Kinase II / Q000378:metabolism*; D002478:Cells, Cultured; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics; D003342:Corpus Striatum / Q000166:cytology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D015151:Immunoblotting / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics*; D011499:Protein Processing, Post-Translational; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*
D006360:Heat-Shock Proteins; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D047390:Casein Kinase II