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Protective up‐regulation of CK2 by mutant huntingtin in cells co‐expressing NMDA receptors
Author(s) -
Fan Mannie M. Y.,
Zhang Hong,
Hayden Michael R.,
Pelech Steven L.,
Raymond Lynn A.
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.05016.x
Subject(s) - huntingtin , protein kinase a , kinase , microbiology and biotechnology , biology , casein kinase 2 , phosphatase , protein phosphatase 1 , mutant , chemistry , biochemistry , phosphorylation , cyclin dependent kinase 2 , gene
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.