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 - Funding Information:
We thank the members of the Zoghbi and Botas laboratories for suggestions and discussions, and V. Brandt for critical reading of the manuscript. This work was supported by the Howard Hughes Medical Institute, the Robert A. and Renee E. Belfer Family Foundation, The Hamill Foundation, The Chapman Foundation, and grant NIH/NINDS R01 NS027699-17; to C.A.L.-R., NIH/NINDS 3R01 NS027699-25S1 and 1K22NS092688-01; to H.Y.Z. and J.B., the Texas Alzheimer’s Research and Care Consortium-Investigator Grant Program; and to I.A.-R., The Darrel K. Royal foundation grant. M.W.C.R. wants to thank The Canadian Institutes of Health Research Fellowship (201210MFE-290072-173743). We also appreciate the assistance of Drs. Jun Qin and Sung Yun Jung at the Mass Spectrometry-Proteomics Core Laboratory (MS-PCL) and the confocal microscopy, neuroconnectivity, and mouse behavioral cores of the Baylor College of Medicine (BCM) Intellectual and Developmental Disabilities Research Center (1U54 HD083092). AD and PSP tissues for this research were provided by the Johns Hopkins University Morris Udall Parkinson’s Disease Center of Excellence (NINDS P50 NS38377) and Alzheimer Disease Research Center (NIA P50 AG05146).
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
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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 -