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

Neuron. 2016 Oct 19;92(2):407-418. Epub 2016 Oct 06

Cristian A Lasagna-Reeves ¹ , Maria de Haro ¹ , Shuang Hao ² , Jeehye Park ¹ , Maxime W C Rousseaux ¹ ,

Cristian A Lasagna-Reeves ¹ , Maria de Haro ¹ , Shuang Hao ² , Jeehye Park ¹ , Maxime W C Rousseaux ¹ , Ismael Al-Ramahi ¹ , Paymaan Jafar-Nejad ¹ , Luis Vilanova-Velez ¹ , Lauren See ¹ , Antonia De Maio ³ , Larissa Nitschke ⁴ , Zhenyu Wu ² , Juan C Troncoso ⁵ , Thomas F Westbrook ⁶ , Jianrong Tang ² , Juan Botas ¹ , Huda Y Zoghbi ⁷

+ et al

Author information

¹ Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
² Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
³ Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, TX 77030, USA; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
⁷ Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: hzoghbi@bcm.edu.

摘要

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.

KEYWORDS: Nuak1, neurodegeneration, tau levels, tau phosphorylation

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