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Inhibiting Phosphorylation and Aggregation of Tau Protein Using R Domain Peptide Mimetics

Alqaeisoom, Najah A.
http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1554907517959837

Abstract Details

2019, Doctor of Philosophy (PhD), Ohio University, Chemistry and Biochemistry (Arts and Sciences).
Tau protein plays a crucial role in stabilizing microtubules inside neuronal axons and maintaining the structural integrity of neurons. Binding of tau to microtubules at tau repeat domains (R) is regulated by phosphorylation. This phosphorylation is regulated by a family of enzymes called kinases. Under pathological conditions, tau is hyperphosphorylated by elevated activity of kinases such as the microtubule affinity-regulating kinase (MARK) proteins, leading to complete detachment of tau, microtubule collapse and ultimately, neuronal cell death. The free, hyper-phosphorylated tau proteins aggregate into insoluble prion-like oligomers which have been implicated in neurodegenerative diseases, including Alzheimer's disease (AD) and frontotemporal dementia. There is currently no treatment to prevent the progression of AD; all medications available today only reduce the symptoms of the disease. Moreover, using small molecule kinase inhibitors as treatment can cause serious negative side effects because of their lack of specificity. The research outlined in this work aims to develop a metabolically stable, selective peptide-based MARK kinase inhibitor that targets MARK proteins. This peptide-based inhibitor, designated tR1, was designed as a direct sequence memetic of the microtubule-binding R1 repeat domain of tau. Here, we show that tR1 peptides can inhibit MARK2 activity and reduce the level of tau phosphorylation in vitro and in cultured rat primary cortical neurons. In the second segment of this project, we attempted to inhibit tau aggregation in vitro using peptide-based aggregation inhibitors. Here, we synthesized peptides designated (an-R3, PHF6, and PHF6*) which mimic nucleating sites in the microtubule binding repeat domain of full-length tau. We hypothesized that these peptides would associate with tau protein and block further tau aggregation. We assessed the ability of these three peptides to inhibit tau aggregation using in vitro heparin-induced tau aggregation assay. The aggregation products were analyzed by SDS-PAGE analysis and by circular dichroism (CD) spectropolarimetry. We provide evidence that the nucleation site located in R3 repeat domain of tau is more prone to aggregation than in R2 repeat domain. Moreover, we show that amphiphilic peptide sequences, in which polar or charged residues alternate with hydrophobic amino acids, are important for tau nucleation and aggregation.
Justin Holub, M. (Advisor)
Marcia Kieliszewski (Committee Member)
Robert Colvin (Committee Member)
Jana Houser (Committee Member)
Jixin Chen (Committee Member)
193 p.
Biochemistry
Tau protein; MARK2; neurodegenerative diseases; peptide-based kinase inhibitors; R1 domain; hTau K18 aggregation; peptide-based aggregation inhibitors; an-R3; PHF6; PHF6 star

Recommended Citations

Citations

  • Alqaeisoom, N. A. (2019). Inhibiting Phosphorylation and Aggregation of Tau Protein Using R Domain Peptide Mimetics [Doctoral dissertation, Ohio University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1554907517959837

    APA Style (7th edition)

  • Alqaeisoom, Najah . Inhibiting Phosphorylation and Aggregation of Tau Protein Using R Domain Peptide Mimetics. 2019. Ohio University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1554907517959837.

    MLA Style (8th edition)

  • Alqaeisoom, Najah . "Inhibiting Phosphorylation and Aggregation of Tau Protein Using R Domain Peptide Mimetics." Doctoral dissertation, Ohio University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1554907517959837

    Chicago Manual of Style (17th edition)

ohiou1554907517959837
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This open access ETD is published by Ohio University and OhioLINK.