Oxidative stress promotes tau dephosphorylation in neuronal cells: the roles of cdk5 and PP1.
Oxidative stress has been demonstrated to produce modifications in several intracellular proteins that lead to alterations in their activities. Alzheimer's disease is related to an increase of oxidative stress markers, which may be an early event in the progression of the disease and neurofibrillary tangles formation. Abnormal phosphorylation of tau has been implicated in the etiopathogenesis of Alzheimer's disease. By using phospho-specific antibodies, we analyzed the changes in tau phosphorylation patterns after treatment of rat hippocampal and SHSY5Y human neuroblastoma cells with H2O2. We found that tau isoforms were hypophosphorylated at the Tau1 epitope after 2 h in the presence of H2O2. The decrease in the phosphorylation levels of tau protein were prevented by pretreatment with N-acetyl-L-cysteine. These changes were shown to depend on the activity of the cdk5/p35 complex, since a 3-fold increase in substrate phosphorylation and a 2-fold increase for the complex association were observed. Also, a decrease in the amount of inhibitor-2 bound to phosphatase PP1 was found in SHSY5Y cells under oxidative stress conditions. This decrease of inhibitor-2 bound to PP1 is due to an increased phosphorylation of the inhibitor-2 protein, thus leading to increased PP1 activity. Therefore, we propose that oxidative stress-induced activation of cdk5 leads to inhibitor-2 phosphorylation, relieving its inhibitory effect on PP1.
Zambrano
Cristian A
CA
Laboratory of Cellular and Molecular Biology, Millennium Institute for Advanced Studies in Cell Biology and Biotechnology, and Department of Biology, Faculty of Sciences, University of Chile, Santiago, Chile.
Egaña
José T
JT
Núñez
Marco T
MT
Maccioni
Ricardo B
RB
González-Billault
Christian
C
D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D051381:Rats; D016875:tau Proteins / Q000378:metabolism*
D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495907:Cdk5 protein, rat; D018844:Cyclin-Dependent Kinases; D010749:Phosphoprotein Phosphatases