Doctor of Philosophy (PhD), Ohio University, 2019, 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 (open full item for complete abstract)

Committee: Justin Holub M. (Advisor); Marcia Kieliszewski (Committee Member); Robert Colvin (Committee Member); Jana Houser (Committee Member); Jixin Chen (Committee Member) Subjects: Biochemistry