Lasagna-Reeves, C.A., de Haro, M., Hao, S., Park, J., Rousseaux, M.W., Al-Ramahi, I., Jafar-Nejad, P., Vilanova-Velez, L., See, L., De Maio, A., Nitschke, L., Wu, Z., Troncoso, J.C., Westbrook, T.F., Tang, J., Botas, J., Zoghbi, H.Y. (2016). Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model.  Neuron 92(2): 407--418.

FBrf0233802

Research paper

Many neurodegenerative proteinopathies share a common pathogenic mechanism: the abnormal accumulation of disease-related proteins. As growing evidence indicates that reducing the steady-state levels of disease-causing proteins mitigates neurodegeneration in animal models, we developed a strategy to screen for genes that decrease the levels of tau, whose accumulation contributes to the pathology of both Alzheimer disease (AD) and progressive supranuclear palsy (PSP). Integrating parallel cell-based and Drosophila genetic screens, we discovered that tau levels are regulated by Nuak1, an AMPK-related kinase. Nuak1 stabilizes tau by phosphorylation specifically at Ser356. Inhibition of Nuak1 in fruit flies suppressed neurodegeneration in tau-expressing Drosophila, and Nuak1 haploinsufficiency rescued the phenotypes of a tauopathy mouse model. These results demonstrate that decreasing total tau levels is a valid strategy for mitigating tau-related neurodegeneration and reveal Nuak1 to be a novel therapeutic entry point for tauopathies.

PMC5745060 (PMC) (EuropePMC)