. Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model. Neuron. 2016 Oct 19;92(2):407-418. Epub 2016 Oct 6 PubMed.

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  1. Cristian Lasagna-Reeves and colleagues in the lab of Huda Zoghbi show—using a variety of model systems for tauopathy—that the serine/threonine-protein kinase Nuak1 plays an important role in neurotoxicity associated with the protein tau. In addition, they demonstrate that Nuak1 associated with pathological accumulation of tau in Alzheimer’s disease and progressive supranuclear palsy (PSP). In line with the importance of Nuak1 in tau-related neurodegeneration, decreasing Nuak1 levels or activity reversed several deficits in a tauopathy mouse model. Using a variety of approaches, Lasagna-Reeves further shows that Nuak1 phosphorylates tau at S356, but not at S262, with phosphorylation of S356 playing a critical role for the proposed role of Nuak1. S356 is located in the C-terminal pseudo-repeat region of tau, which is both important for pathogenic aggregation and also binds to microtubules (MT). Identification of a kinase, which selectively phosphorylates S356, might therefore open new possibilities to influence both the physiological and pathological function of tau.

    From a mechanistic point of view, the study raises an intriguing question about the role of S356 as a phosphorylation site when compared to other tau phosphorylation sites such as S262. For example, we (Schwalbe et al., 2013) have shown that phosphorylation of tau at S356 does not completely abolish binding to microtubules, but diminishes the MT-binding contribution of pseudo-repeat R4 and thus can contribute to an overall decrease in MT-affinity. At the same time, much less is known about the contribution of R4 and in particular phosphorylation at S356 for MT assembly. It will also be interesting to address in the future how Nuak1 achieves selectivity towards S356 when compared to S262, because both residues are part of a KIGS-motif, which can be phosphorylated 100 percent by MARK2 (Schwalbe et al., 2013). The selective nature of Nuak1 phosphorylation at S356 also raises the question about the potential contribution of individual pseudo-repeats and individual phosphorylation sites within the four repeats of tau for tau-mediated neurotoxicity.

    References:

    . Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2. Biochemistry. 2013 Dec 17;52(50):9068-79. Epub 2013 Nov 22 PubMed.

    View all comments by Markus Zweckstetter
  2. In this interesting study by Dr. Huda Zoghbi and colleagues, the authors showed that the AMPK-related kinase Nuak1 regulates tau toxicity through controlling its stability in mammalian cells and in Drosophila and mouse tauopathy models. The authors further showed that Nuak1 does so by phosphorylating tau at the S356 site in the fourth microtubule-binding domain (MBD). Functionally, 50 percent reduction of Nuak1 activity effectively reduced tau phosphorylation and stability and the neuropathological and behavioral phenotypes in the P301S tauopathy mouse model. The clinical relevance of the study is highlighted by the analysis of Alzheimer’s disease (AD) and progressive surpranuclear palsy patient brain samples, where Nuak1 is found associated with insoluble tau in neurofibrillary tangles (NFT).

    This study, together with previous studies on phosphorylation of the MBD by PAR-1, another AMPK-related kinase, highlights the importance of tau phosphorylation at S262 and S365 in conferring tau toxicity (Nishimura et al., 2004), stability (Ando et al., 2016; Ando et al., 2016), and in mediating the toxic effect of Aβ42 (Yu et al., 2012; Ando et al., 2016), and emphasizes the importance of AMPK-related kinase in tau pathogenesis. The phosphorylation of the MBD by these kinases early in the disease process may lead to tau dissociation from the microtubule, its stabilization, hyperphosphorylation by downstream kinases, and the formation of NFTs. Therapeutic targeting of these AMPK-related kinases, or their upstream activating kinase LKB1, which has been shown to regulate tau toxicity through PAR-1 in Drosophila (Wang et al., 2007), may offer a new way to combat AD and related tauopathies, for which there are currently no effective treatment option.

    References:

    . PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila. Cell. 2004 Mar 5;116(5):671-82. PubMed.

    . Tau phosphorylation at Alzheimer's disease-related Ser356 contributes to tau stabilization when PAR-1/MARK activity is elevated. Biochem Biophys Res Commun. 2016 Sep 16;478(2):929-34. Epub 2016 Aug 9 PubMed.

    . Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity. PLoS Genet. 2016 Mar;12(3):e1005917. Epub 2016 Mar 29 PubMed.

    . A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines. Hum Mol Genet. 2012 Mar 15;21(6):1384-90. PubMed.

    . Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity. PLoS Genet. 2016 Mar;12(3):e1005917. Epub 2016 Mar 29 PubMed.

    . Activation of PAR-1 kinase and stimulation of tau phosphorylation by diverse signals require the tumor suppressor protein LKB1. J Neurosci. 2007 Jan 17;27(3):574-81. PubMed.

    View all comments by Bingwei Lu

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  1. New Target for Tauopathies? Blocking Nuak1 Could Reduce Tau Build-Up