A new TAO kinase inhibitor reduces tau phosphorylation at sites associated with neurodegeneration in human tauopathies

Abstract

In Alzheimer’s disease (AD) and related tauopathies, the microtubule-associated protein tau is highly phosphorylated and aggregates to form neurofibrillary tangles that are characteristic of these neurodegenerative diseases. Our previous work has demonstrated that the thousand-and-one amino acid kinases (TAOKs) 1 and 2 phosphorylate tau on more than 40 residues in vitro. Here we show that TAOKs are phosphorylated and active in AD brain sections displaying mild (Braak stage II), intermediate (Braak stage IV) and advanced (Braak stage VI) tau pathology and that active TAOKs co-localise with both pre-tangle and tangle structures. TAOK activity is also enriched in pathological tau containing sarkosyl-insoluble extracts prepared from AD brain. Two new phosphorylated tau residues (T123 and T427) were identified in AD brain, which appear to be targeted specifically by TAOKs. A new small molecule TAOK inhibitor (Compound 43) reduced tau phosphorylation on T123 and T427 and also on additional pathological sites (S262/S356 and S202/T205/S208) in vitro and in cell models. The TAOK inhibitor also decreased tau phosphorylation in differentiated primary cortical neurons without affecting markers of synapse and neuron health. Notably, TAOK activity also co-localised with tangles in post-mortem frontotemporal lobar degeneration (FTLD) brain tissue. Furthermore, the TAOK inhibitor decreased tau phosphorylation in induced pluripotent stem cell derived neurons from FTLD patients, as well as cortical neurons from a transgenic mouse model of tauopathy (Tau35 mice). Our results demonstrate that abnormal TAOK activity is present at pre-tangles and tangles in tauopathies and that TAOK inhibition effectively decreases tau phosphorylation on pathological sites. Thus, TAOKs may represent a novel target to reduce or prevent tau-associated neurodegeneration in tauopathies.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0539-8) contains supplementary material, which is available to authorized users.

De Novo Variants in TAOK1 Cause Neurodevelopmental Disorders

“…16,17 Using patientderived fibroblast cells from individual 7 and two different control fibroblast lines, we performed immunoblotting against phosphorylated tau protein and showed that there was no detectable phosphorylated tau (p-tau) protein in the mutant fibroblasts ( Figure 2D). In accordance with previous observations, 18 our results demonstrate that decreased TAO1 kinase protein levels effectively decrease tau phosphorylation in fibroblasts of a TAOK1 mutation carrier. Notably, higher p-tau levels have been shown to elongate the mitochondria as a result of delocalization of dynamin related protein 1 (DRP1), the fission protein for mitochondria.…”

The Diverse Roles of TAO Kinases in Health and Diseases

“…TAOKs modulate the dynamics and organization of several cytoskeleton components [ 29 , 30 , 31 ]. TAOKs are activated catalytically during mitosis and neuritogenesis [ 32 , 33 , 34 , 35 , 36 ]. By phosphorylation of microtubule-binding proteins including tau, TAOK1 induces microtubule instability by causing dissociation of tau from microtubules, which results in their disassembly [ 30 , 31 , 37 ] ( Figure 3 A).…”

Tao Negatively Regulates BMP Signaling During Neuromuscular Junction Development in Drosophila

“…Mammalian Tao (also known as MARKK) activates Par‐1/MARK to inhibit microtubule stability, notably in neuronal cultures (Biernat et al , ; Timm et al , ). However, in adult Drosophila brains, Tao inhibits Par‐1 and positively regulates the microtubule‐stabilizing protein Tau during axon outgrowth and neurodegeneration (Wang et al , ; King et al , ), and there is also evidence that Tao‐family kinases can directly phosphorylate Tau (Giacomini et al , ). Interestingly, BMP signaling also destabilizes microtubules via Spartin (Nahm et al , ).…”