Activation of a neurofilament kinase, a tau kinase, and a tau phosphatase by decreased ATP levels in nerve growth factor-differentiated PC-12 cells.
Brain pathology in Alzheimer disease and in aged controls shows hyperphosphorylation of tau and of neurofilament proteins. Roder and Ingram [Roder, H.M. & Ingram, V.M. (1991) J. Neurosci. 11, 3325-3343 and Roder, H.M., Eden, P.A. & Ingram, V.M. (1993) Biochem. Biophys. Res. Commun. 193, 639-647] previously reported that the brain protein kinase PK40erk can hyperphosphorylate both tau and neurofilaments and interestingly, is strongly inhibited by ATP uncomplexed with Mg2+. We now report that the mitochondrial uncoupler carbonyl cyanide p-trifluoro-methoxyphenylhydrazone decreases ATP levels in rat pheochromacytoma (PC-12) cells differentiated with nerve growth factor and activates a neurofilament kinase, a tau kinase, and, unexpectedly, a tau phosphatase--either PP1 or PP2A. Such aberrant modulation of protein phosphorylation patterns could be the common biochemical basis for senile dementia and for Alzheimer disease and could explain the late-onset etiology of both conditions.
Bush
M L
ML
Department of Biology, Massachusetts Institute of Technology, Cambridge 02139.
Miyashiro
J S
JS
Ingram
V M
VM
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology*; D002454:Cell Differentiation; D004789:Enzyme Activation; D004988:Ethers, Cyclic / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016900:Neurofilament Proteins / Q000378:metabolism; D019319:Okadaic Acid; D016716:PC12 Cells; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D016875:tau Proteins / Q000378:metabolism
D004988:Ethers, Cyclic; D009414:Nerve Growth Factors; D016900:Neurofilament Proteins; D016875:tau Proteins; D019319:Okadaic Acid; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D000255:Adenosine Triphosphate; D011494:Protein Kinases; C084357:neurofilament-associated kinase; D017346:Protein Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; C080888:tau-protein kinase; D010749:Phosphoprotein Phosphatases