期刊
NEURON
卷 92, 期 2, 页码 407-418出版社
CELL PRESS
DOI: 10.1016/j.neuron.2016.09.022
关键词
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资金
- Howard Hughes Medical Institute
- Robert A. and Renee E. Belfer Family Foundation
- Hamill Foundation
- Chapman Foundation
- NIH/NINDS [R01 NS027699-17, 3R01 NS027699-25S1, 1K22NS092688-01]
- Texas Alzheimer's Research and Care Consortium-Investigator Grant Program
- Darrel K. Royal foundation
- Canadian Institutes of Health Research [201210MFE-290072-173743]
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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