ArticlePloS one2020
Acute inhibition of the CNS-specific kinase TTBK1 significantly lowers tau phosphorylation at several disease relevant sites.
Article in PloS one, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 24 citations in OpenAlex.
- Computational Design of Novel Tau-Tubulin Kinase 1 Inhibitors for Neurodegenerative Diseases.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Antisense oligonucleotide-based targeting of Tau-tubulin kinase 1 prevents hippocampal accumulation of phosphorylated tau in PS19 tauopathy mice.Acta neuropathologica communications · 2023Article
- Does modulation of tau hyperphosphorylation represent a reasonable therapeutic strategy for Alzheimer's disease? From preclinical studies to the clinical trials.Molecular psychiatry · 2023Review
- Modulation of tau tubulin kinases (TTBK1 and TTBK2) impacts ciliogenesis.Scientific reports · 2023Article
- Elucidation of the GSK3α Structure Informs the Design of Novel, Paralog-Selective Inhibitors.ACS chemical neuroscience · 2023Article
- Role of protein phosphorylation in cell signaling, disease, and the intervention therapy.MedComm · 2022Review
- Identification and Utilization of a Chemical Probe to Interrogate the Roles of PIKfyve in the Lifecycle of β-Coronaviruses.Journal of medicinal chemistry · 2022Article
- CK2 and protein kinases of the CK1 superfamily as targets for neurodegenerative disorders.Frontiers in molecular biosciences · 2022Review
- Tau phosphorylation and OPA1 proteolysis are unrelated events: Implications for Alzheimer's Disease.Biochimica et biophysica acta. Molecular cell research · 2021Article
- Tau Protein Interaction Partners and Their Roles in Alzheimer's Disease and Other Tauopathies.International journal of molecular sciences · 2021Review
- Mechanisms of Regulation and Diverse Activities of Tau-Tubulin Kinase (TTBK) Isoforms.Cellular and molecular neurobiology · 2021Article
- Tauopathies: Deciphering Disease Mechanisms to Develop Effective Therapies.International journal of molecular sciences · 2020Review
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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