Acute inhibition of the CNS-specific kinase TTBK1 significantly lowers tau phosphorylation at several disease relevant sites

• DOI: 10.1371/journal.pone.0228771
• Publication Date: 2020-04-07T17:24:26Z
• Authors: Gregory M. Dillon; Jaclyn L. Henderson; Channa Bao; John A. Joyce; Michael Calhoun; Brenda Amaral; Kristopher W. King; Bekim Bajrami; Dania Rabah
• Keywords: Kinome; Tau protein; Cyclin-dependent kinase 5

Hyperphosphorylated tau protein is a pathological hallmark of numerous neurodegenerative diseases and the level pathology correlated with degree cognitive impairment. Tau hyper-phosphorylation thought to be an early initiating event in cascade leading toxicity neuronal death. Inhibition phosphorylation therefore represents attractive therapeutic strategy. However, widespread expression most kinases promiscuity their substrates, along poor selectivity kinase inhibitors, have resulted systemic toxicities that limited advancement inhibitors into clinic. We focused on CNS-specific kinase, TTBK1, investigated whether selective inhibition this could represent viable approach targeting disease. In current study, we demonstrate TTBK1 regulates using overexpression or knockdown heterologous cells primary neurons. Importantly, find TTBK1-specific leads loss normal function including decrease tau-tubulin binding deficits tubulin polymerization. then describe use novel, small molecule antagonist, BIIB-TTBK1i, study acute effects vivo. substantial lowering at multiple sites implicated disease, suggesting may exciting new search for disease therapies.