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

Cristian 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 journalArticle

24 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Tauopathies
Drosophila
Progressive Supranuclear Palsy
Phenotype
Haploinsufficiency
Diptera
Fruit
Alzheimer Disease
Proteins
Animal Models
Phosphorylation
Pathology
Genes
Therapeutics
AMP-activated protein kinase kinase
Inhibition (Psychology)

Keywords

  • neurodegeneration
  • Nuak1
  • tau levels
  • tau phosphorylation

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Lasagna Reeves, C., de Haro, M., Hao, S., Park, J., Rousseaux, M. W. C., Al-Ramahi, I., ... Zoghbi, H. Y. (2016). Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model. Neuron, 92(2), 407-418. https://doi.org/10.1016/j.neuron.2016.09.022

Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model. / Lasagna Reeves, Cristian; de Haro, Maria; Hao, Shuang; Park, Jeehye; Rousseaux, Maxime W C; Al-Ramahi, Ismael; Jafar-Nejad, Paymaan; Vilanova-Velez, Luis; See, Lauren; De Maio, Antonia; Nitschke, Larissa; Wu, Zhenyu; Troncoso, Juan C.; Westbrook, Thomas F.; Tang, Jianrong; Botas, Juan; Zoghbi, Huda Y.

In: Neuron, Vol. 92, No. 2, 19.10.2016, p. 407-418.

Research output: Contribution to journalArticle

Lasagna Reeves, C, de Haro, M, Hao, S, Park, J, Rousseaux, MWC, Al-Ramahi, I, Jafar-Nejad, P, Vilanova-Velez, L, See, L, De Maio, A, Nitschke, L, Wu, Z, Troncoso, JC, Westbrook, TF, Tang, J, Botas, J & Zoghbi, HY 2016, 'Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model', Neuron, vol. 92, no. 2, pp. 407-418. https://doi.org/10.1016/j.neuron.2016.09.022
Lasagna Reeves, Cristian ; de Haro, Maria ; Hao, Shuang ; Park, Jeehye ; Rousseaux, Maxime W C ; Al-Ramahi, Ismael ; Jafar-Nejad, Paymaan ; Vilanova-Velez, Luis ; See, Lauren ; De Maio, Antonia ; Nitschke, Larissa ; Wu, Zhenyu ; Troncoso, Juan C. ; Westbrook, Thomas F. ; Tang, Jianrong ; Botas, Juan ; Zoghbi, Huda Y. / Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model. In: Neuron. 2016 ; Vol. 92, No. 2. pp. 407-418.
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