TY - JOUR
T1 - Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model
AU - Lasagna-Reeves, Cristian A.
AU - de Haro, Maria
AU - Hao, Shuang
AU - Park, Jeehye
AU - Rousseaux, Maxime W.C.
AU - Al-Ramahi, Ismael
AU - Jafar-Nejad, Paymaan
AU - Vilanova-Velez, Luis
AU - See, Lauren
AU - De Maio, Antonia
AU - Nitschke, Larissa
AU - Wu, Zhenyu
AU - Troncoso, Juan C.
AU - Westbrook, Thomas F.
AU - Tang, Jianrong
AU - Botas, Juan
AU - Zoghbi, Huda Y.
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/10/19
Y1 - 2016/10/19
N2 - 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.
AB - 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.
KW - Nuak1
KW - neurodegeneration
KW - tau levels
KW - tau phosphorylation
UR - http://www.scopus.com/inward/record.url?scp=84992025495&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84992025495&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2016.09.022
DO - 10.1016/j.neuron.2016.09.022
M3 - Article
C2 - 27720485
AN - SCOPUS:84992025495
SN - 0896-6273
VL - 92
SP - 407
EP - 418
JO - Neuron
JF - Neuron
IS - 2
ER -