Dr. Heidi Scrable died on February 13, 2013 after a prolonged battle with a disease. Although she participated in all intellectual aspects of this work, she never saw the final version of this manuscript. She was a friend and collaborator. She will be missed.
P44, the ‘longevity-assurance’ isoform of P53, regulates tau phosphorylation and is activated in an age-dependent fashion
Article first published online: 25 FEB 2014
© 2014 The Authors. Aging Cell Published by the Anatomical Society and John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Volume 13, Issue 3, pages 449–456, June 2014
How to Cite
Pehar, M., Ko, M. H., Li, M., Scrable, H. and Puglielli, L. (2014), P44, the ‘longevity-assurance’ isoform of P53, regulates tau phosphorylation and is activated in an age-dependent fashion. Aging Cell, 13: 449–456. doi: 10.1111/acel.12192
- Issue published online: 23 MAY 2014
- Article first published online: 25 FEB 2014
- Accepted manuscript online: 17 DEC 2013 05:15AM EST
- Manuscript Accepted: 1 DEC 2013
- Department of Veterans Affairs
- Alzheimer's disease;
- cognitive decline;
p44 is a short isoform of p53 with ‘longevity-assurance’ activity. Overexpression of p44 in the mouse (p44+/+ transgenic mice) causes a progeroid phenotype that mimics an accelerated form of aging. The phenotype includes abnormal phosphorylation of the microtubule-binding protein tau, synaptic deficits, and cognitive decline. Genetic engineering demonstrated that the phosphorylation status of tau acts upstream of the synaptic deficits. Here, we provide evidence that p44 promotes the phosphorylation of tau in the mouse. Specifically, we show that p44 binds to the promoter of tau kinases Dyrk1A, GSK3β, Cdk5, p35, and p39 and activates their transcription. The upregulation of the above kinases is followed by increased phosphorylation of tau. Finally, we show that p44 is preferentially found in the nucleus and that its levels increase with age in the mouse brain. Taken together, these results suggest that an imbalance in the p53:p44 ratio might be involved with the altered tau metabolism that characterizes aging.