Acute inhibition of the CNS-specific kinase TTBK1 significantly lowers tau phosphorylation at several disease relevant sites
| Autor: | Dania Rabah, Channa Bao, Gregory M Dillon, Jaclyn L. Henderson, Bekim Bajrami, Michael Calhoun, Kristopher W King, Brenda Amaral, John A. Joyce |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Central Nervous System
Male 0301 basic medicine Kinase Inhibitors Hypothermia Pathology and Laboratory Medicine Alzheimer's Disease Biochemistry Microtubules Polymerization 0302 clinical medicine Animal Cells Central Nervous System Diseases Tubulin Medicine and Health Sciences Post-Translational Modification Phosphorylation Enzyme Inhibitors Cytoskeleton Cells Cultured Neurons Gene knockdown Multidisciplinary biology Kinase Chemistry Chemical Reactions Neurodegenerative Diseases Transfection Neurology Organ Specificity Physical Sciences Medicine Cellular Structures and Organelles Cellular Types Research Article Protein Binding Science Tau protein Heterologous tau Proteins Protein Serine-Threonine Kinases Small Molecule Libraries 03 medical and health sciences Signs and Symptoms Tubulins Diagnostic Medicine In vivo Mental Health and Psychiatry mental disorders Animals Protein Kinase Inhibitors Antagonist Biology and Life Sciences Proteins Cell Biology Polymer Chemistry Mice Inbred C57BL Cytoskeletal Proteins 030104 developmental biology Cellular Neuroscience Enzymology biology.protein Cancer research Dementia 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | PLoS ONE, Vol 15, Iss 4, p e0228771 (2020) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Hyperphosphorylated tau protein is a pathological hallmark of numerous neurodegenerative diseases and the level of tau pathology is correlated with the degree of cognitive impairment. Tau hyper-phosphorylation is thought to be an early initiating event in the cascade leading to tau toxicity and neuronal death. Inhibition of tau phosphorylation therefore represents an attractive therapeutic strategy. However, the widespread expression of most kinases and promiscuity of their substrates, along with poor selectivity of most kinase inhibitors, have resulted in systemic toxicities that have limited the advancement of tau kinase inhibitors into the clinic. We therefore focused on the CNS-specific tau kinase, TTBK1, and investigated whether selective inhibition of this kinase could represent a viable approach to targeting tau phosphorylation in disease. In the current study, we demonstrate that TTBK1 regulates tau phosphorylation using overexpression or knockdown of this kinase in heterologous cells and primary neurons. Importantly, we find that TTBK1-specific phosphorylation of tau leads to a loss of normal protein function including a decrease in tau-tubulin binding and deficits in tubulin polymerization. We then describe the use of a novel, selective small molecule antagonist, BIIB-TTBK1i, to study the acute effects of TTBK1 inhibition on tau phosphorylation in vivo. We demonstrate substantial lowering of tau phosphorylation at multiple sites implicated in disease, suggesting that TTBK1 inhibitors may represent an exciting new approach in the search for neurodegenerative disease therapies. |
| Databáze: | OpenAIRE |
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