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

Neuron. 2016 Oct 19;92(2):407-418. doi: 10.1016/j.neuron.2016.09.022. Epub 2016 Oct 6.


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.

Keywords: Nuak1; neurodegeneration; tau levels; tau phosphorylation.

MeSH terms

  • Alzheimer Disease / genetics
  • Animals
  • Behavior, Animal*
  • Cell Line, Tumor
  • Conditioning, Psychological
  • Disease Models, Animal
  • Drosophila
  • Fear
  • Fluorescent Antibody Technique
  • Humans
  • Immunoblotting
  • Mice
  • Phosphorylation / genetics
  • Protein Kinases / genetics*
  • Repressor Proteins / genetics*
  • Supranuclear Palsy, Progressive / genetics
  • Tauopathies / genetics*
  • tau Proteins / metabolism*


  • Repressor Proteins
  • tau Proteins
  • Protein Kinases
  • NUAK1 protein, human
  • NUAK1 protein, mouse