Tau aggregation
Tau tubulin kinases (TTBKs) activate cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3 beta (GSK3b), two tau kinases, and phosphorylate collapsin response mediator protein 2 (pCRMP2), which interacts with pTau (yellow, left). The pCRMP2 or pTau complex moves back to cell soma (left) instead of axonal termina (right). Dysfunction of kinesin induces axonal degeneration.
Tau-tubulin kinase 1: Therapeutic target of Alzheimer's disease
Dr. Tsuneya Ikezu cloned a neuron-specific tau kinase — tau-tubulin kinase 1 (TTBK1) — from the human brain tissue cDNA library and characterized the role of TTBK1 in tau aggregation in the context of Alzheimer's disease pathogenesis. While intracellular accumulation of phosphorylated tau is the diagnostic marker of Alzheimer's disease, to date no drug has been developed that successfully targets tau phosphorylation.
A Molecular Neurotherapeutics lab team led by Seiko Ikezu, M.D., developed antisense oligonucleotide to target mouse Ttbk1, which shows a therapeutic effect in PS19 tau mice.
References
- Yukawa K, Yamamoto-Mcguire S, Cafaro L, Hong C, Kamme F, Ikezu T, Ikezu S. Antisense oligonucleotide-based targeting of Tau-tubulin kinase 1 prevents hippocampal accumulation of phosphorylated tau in PS19 tauopathy mice.
Acta Neuropathologica Communications. 2023; doi:10.1186/s40478-023-01661-3.
- Sato S, Xu J, Okuyama S, Martinez LB, Walsh SM, Jacobsen MT, Swan RJ, Schlautman JD, Ciborowski P, Ikezu T. Spatial learning impairment, enhanced CDK5/p35 activity and downregulation of NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1. Journal of Neuroscience. 2008; doi:10.1523/JNEUROSCI.3417-08.2008.
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