Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model

Cristian A. Lasagna-Reeves, Maria de Haro, Shuang Hao, Jeehye Park, Maxime W.C. Rousseaux, Ismael Al-Ramahi, Paymaan Jafar-Nejad, Luis Vilanova-Velez, Lauren See, Antonia De Maio, Larissa Nitschke, Zhenyu Wu, Juan C. Troncoso, Thomas F. Westbrook, Jianrong Tang, Juan Botas, Huda Y. Zoghbi

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)407-418
Number of pages12
JournalNeuron
Volume92
Issue number2
DOIs
StatePublished - Oct 19 2016

Keywords

  • Nuak1
  • neurodegeneration
  • tau levels
  • tau phosphorylation

ASJC Scopus subject areas

  • Neuroscience(all)

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