Editors' ChoiceNeurodegeneration

A tauopathy kinase

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Sci. Signal.  25 Oct 2016:
Vol. 9, Issue 451, pp. ec252
DOI: 10.1126/scisignal.aal2595

The accumulation of phosphorylated tau in neurofibrillary tangles in the brain is associated with the development of various neurodegenerative tauopathies, including Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP). Using animal models, Lasagna-Reeves et al. found that inhibitors of the kinase NUAK1, which is related to the energy-sensing kinase AMPK, might slow or prevent tau accumulation in the brain. An RNA interference screen of the kinome in cultured medulloblastoma cells expressing fluorescent-tagged tau along with a genetic screen in a Drosophila tauopathy model identified 16 kinases that potentially contributed to tau accumulation and subsequent neurotoxicity. Among these kinases, a role for NUAK1 was confirmed with additional assays in cells, flies, and mice. Compared with age-matched controls, postmortem brain tissue from AD and PSP patients had increased abundance of NUAK1 protein but not mRNA, suggesting the stability of NUAK1 protein increased in these diseases. NUAK1 colocalized with tau neurofibrillary tangles and was present in the insoluble fractions of brain tissue only from AD and PSP patients. In vitro kinase assays, mass spectrometry, and transfection assays in neuroblastoma cells revealed that NUAK1 phosphorylated tau at Ser356, which increased the half-life of tau protein and promoted its accumulation in cells. Inhibiting NUAK1 with WZ4003 decreased the abundance of phosphorylated tau in cultured neuroblastoma cells. Halving the gene dosage of NUAK1 in P301S transgenic mice decreased the abundance of phosphorylated tau in the brain, increased in vivo long-term potentiation (a form of synaptic plasticity associated with learning and memory) in the hippocampus, and improved the animals’ performance on various memory retention tests. The findings suggest that targeting NUAK1 might slow the progression of tauopathies.

C. A. Lasagna-Reeves, M. de Haro, S. Hao, J. Park, M. W. C. Rousseaux, I. Al-Ramahi, P. Jafar-Nejad, L. Vilanova-Velez, L. See, A. De Maio, L. Nitschke, Z. Wu, J. C. Troncoso, T. F. Westbrook, J. Tang, J. Botas, H. Y. Zoghbi, Reduction of Nuak1 decreases tau and reverses phenotypes in a tauopathy mouse model. Neuron 92, 407–418 (2016). [PubMed]