P44, the ‘longevity-assurance’ isoform of P53, regulates tau phosphorylation and is activated in an age-dependent fashion

Authors

  • Mariana Pehar,

    1. Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
    Current affiliation:
    1. Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA
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    • Both authors are co-first authors.
  • Mi Hee Ko,

    1. Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
    Current affiliation:
    1. Division of Bioresources Research, Jeju Technopark, Jeju Biodiversity Research Institute, Seogwipo-si, Jeju-do, Korea
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    • Both authors are co-first authors.
  • Mi Li,

    1. Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
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  • Heidi Scrable,

    1. Robert and Arlene Kogod Center on Aging, Division of Experimental Pathology, Mayo Clinic, Rochester, MN, USA
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    • 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.
  • Luigi Puglielli

    Corresponding author
    1. Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
    2. Geriatric Research Education Clinical Center, VA Medical Center, 2500 Overlook Terrace, Madison, WI, USA
    • Correspondence

      Luigi Puglielli, University of Wisconsin-Madison, VAH-GRECC 11G, 2500 Overlook Terrace, Madison, WI 53705, USA. Tel.: +1 608 2561901 (ext. 11569); fax: +1 608 2807291; e-mail: lp1@medicine.wisc.edu

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Summary

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.

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