Activation of the ERK and JNK signaling pathways caused by neuron-specific inhibition of PP2A in transgenic mice.
A reduced activity of protein phosphatase 2A (PP2A) has been shown in brains of patients with Alzheimer's disease (AD), a neurodegenerative disorder characterized histopathologically by amyloid plaques and neurofibrillary tangles. Tau, as the principal component of neurofibrillary tangles, can be hyperphosphorylated by a reduced activity of PP2A in vitro and by pharmacological approaches, suggesting a crucial role of PP2A in tangle formation. To dissect the role of PP2A in vivo, we previously generated transgenic mice with chronically reduced PP2A activity by expressing a dominant-negative mutant form of the PP2A catalytic subunit Calpha, L199P, under the control of a neuron-specific promoter. In these mice, endogenous tau is phosphorylated at the epitopes Ser202/Thr205 and Ser422. In vitro, these tau phospho-epitopes can be phosphorylated by the kinases ERK and JNK, and the kinases themselves are negatively regulated by PP2A. In this study, we show that chronic inhibition of PP2A activity in L199P transgenic mice causes the activation of ERK and JNK as demonstrated by the phosphorylation and nuclear accumulation of the ERK and JNK substrates, Elk-1 and c-Jun. TUNEL staining revealed that activated JNK signaling was not associated with cell death. Our findings imply that PP2A is a negative regulator of the ERK and JNK signaling pathways in vivo, suggesting that in AD, tau hyperphosphorylation may be caused in part by PP2A dysfunction.
Kins
Stefan
S
Division of Psychiatry Research, University of Zürich, August Forel Strasse 1, 8008 Zürich, Switzerland. goetz@bli.unizh.ch
Kurosinski
Pascal
P
Nitsch
Roger M
RM
Götz
Jürgen
J
D000818:Animals; D017209:Apoptosis; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D009474:Neurons / Q000201:enzymology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014018:Tissue Distribution; D016875:tau Proteins / Q000378:metabolism
D007527:Isoenzymes; D016755:Proto-Oncogene Proteins c-jun; D016875:tau Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2