학술논문
Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model.
Document Type
Article
Author
Lasagna-Reeves, Cristian A.; 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.
Source
Subject
*PHENOTYPES
*GENETICS
*NEURODEGENERATION
*ANIMAL models in research
*PHOSPHORYLATION
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Language
ISSN
0896-6273
Abstract
Summary 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. [ABSTRACT FROM AUTHOR]