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Inhibiting Phosphorylation of Tau (τ) Proteins at Ser262 Using Peptide-Based R1 Domain Mimetics

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Abstract

The microtubule-associated protein tau (τ) is a phosphoprotein that is crucial for regulating microtubule dynamics. Tau is highly enriched in neurons, where it functions by binding tubulin and stabilizing axonal microtubules. Phosphorylation of tau within its microtubule-binding repeat (R) domains significantly reduces its affinity for tubulin, leading to a loss in microtubule stability. In neurons, dysregulated kinase activity often results in the formation of hyper-phosphorylated tau isoforms that remain permanently detached from microtubules. If left untreated, hyper-phosphorylated tau can aggregate into insoluble, prion-like oligomers that contribute to the pathogenesis of neurodegenerative disease. Consequently, there is considerable interest in developing inhibitors that reduce levels of hyper-phosphorylated tau in neurons. In this study, we have generated a synthetic peptide mimetic (tR1) of the tau R1 domain as an inhibitor of microtubule-affinity regulating kinase 2 (MARK2). In vitro assays showed that tR1 inhibits the MARK2-mediated phosphorylation of tau within its R1 domain at Ser262, a residue critical for favorable tau-tubulin interactions. We also demonstrate that tR1 peptides are > 90% stable up to 24 h in neurobasal medium and RPMI media supplemented with human serum. Uptake experiments in cultured rat primary cortical neurons indicate that tR1 is internalized through an energy-dependent mechanism and can be delivered to the cytoplasm when co-treated with bafilomycin A1 or chloroquine. Furthermore, we show tR1 inhibits phosphorylation of endogenous tau at Ser262 in cultured neurons following activation of intracellular kinases. This inhibitory effect was selective for kinases that phosphorylate tau at Ser262, as tR1 did not inhibit tau phosphorylation at Thr231. Collectively, these results establish tR1 as a highly-stable, peptide-based kinase inhibitor that reduces the level of phosphorylated tau proteins in neurons.

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Acknowledgements

This work was supported in part by the Department of Chemistry and Biochemistry, the Department of Biological Sciences, the Edison Biotechnology Institute, the College of Arts and Sciences, and the Vice President for Research at Ohio University. Additional funding for this research came from the Ohio Musculoskeletal and Neurological Institute (OMNI) and the Ohio University Research Counsel (proposal #17−15) at Ohio University. Author Najah Alqaeisoom was supported by the Saudi Arabian Cultural Mission (SACM, #397056). The authors would like to thank Professor Kevin G. Moffat for supplying the pProEX-HTa-Myc-K18 plasmid.

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  1. Najah Alqaeisoom and Cheng Qian have contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, Ohio University, Athens, OH, 45701, USA

    Najah Alqaeisoom, Danushka Arachchige & Justin M. Holub

  2. Department of Biological Sciences, Ohio University, Athens, OH, 45701, USA

    Cheng Qian & Robert A. Colvin

  3. Molecular and Cellular Biology Program, Ohio University, Athens, OH, 45701, USA

    Robert A. Colvin & Justin M. Holub

  4. Edison Biotechnology Institute, Ohio University, Athens, OH, 45701, USA

    Justin M. Holub

  5. Biochemistry Research Facility #108, 350 W. State St., Athens, OH, 45701, USA

    Justin M. Holub

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  1. Najah Alqaeisoom
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Correspondence to Justin M. Holub.

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The care and use of all animals used in this work adhered to the American Physiological Society’s Guiding Principles in the Care and Use of Animals. All experimental procedures utilized herein were approved by the Ohio University Institutional Animal Care and Use Committee. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Alqaeisoom, N., Qian, C., Arachchige, D. et al. Inhibiting Phosphorylation of Tau (τ) Proteins at Ser262 Using Peptide-Based R1 Domain Mimetics. Int J Pept Res Ther 25, 447–463 (2019). https://doi.org/10.1007/s10989-018-9689-6

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