Drug Discovery Opinion

Neurofibrillary tangles (NFT) are a hallmark of Alzheimer’s disease (AD) and correlate strongly with synaptic loss and severity of dementia. NFT appear to be attributable, at least in part, to hyperphosphorylation of the microtubule-stabilising protein, tau. Numerous phosphorylation sites have been associated with tau dysfunction and neurodegeneration: phosphorylation on Ser²⁶² has been shown to occur early in disease progression and to significantly reduce the affinity of tau for microtubules. Although hyperphosporylation at other sites is likely necessary for neurodegeneration, increased phosphorylation at Ser²⁶² is an important early step and firm identification of the kinase(s) responsible for phosphorylation at this position could provide new targets for disease-modifying treatments. Numerous kinases have been reported to phosphorylate tau at Ser²⁶² in vitro, but the role of these kinases on neurofibrillary tangle formation in vivo remains unclear.

Using a loss of function high throughput RNAi approach to screen the entire human kinome, a team led by scientists at the Translational Genomics Research Institute (TGen) have now identified three new kinases, dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), A-kinase anchor protein 13 (AKAP13), and eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) that contribute to hyperphosphorylation of tau. Whereas DYRK1A and AKAP13 appear to be specifically involved in tau phosphorylation pathways, the effects of EIF2AK2 may result from alterations in tau protein expression.

If further studies in neuronal cell lines and in vivo models of AD and tauopathies confirm the importance of these kinases in disease pathology, they would represent novel targets for disease-modifying treatments for AD.

The study is published in BMC Genomics.

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