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

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2016 Oct 11

PMID 27720485

Citations 81

Authors

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

Affiliations

Soon will be listed here.

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.

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