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
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.
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.
Neuron. 2016 Oct 19;92(2):407-418. doi: 10.1016/j.neuron.2016.09.022. Epub 2016 Oct 6.
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.
与疾病相关的蛋白质异常积累。越来越多的证据表明，降低致病蛋白的稳态水平可减轻动物模型中的神经退行性变，因此我们开发了一种策略来筛选能够降低tau蛋白水平的基因，tau蛋白的积累会导致阿尔茨海默病（AD）和进行性核上性麻痹（PSP）的病理改变。通过整合基于细胞的平行筛选和果蝇遗传学筛选，我们发现tau蛋白水平受Nuak1调控，Nuak1是一种与AMPK相关的激酶。Nuak1通过特异性磷酸化Ser356来稳定tau蛋白。在果蝇中抑制Nuak1可抑制表达tau蛋白的果蝇的神经退行性变，而Nuak1单倍体不足可挽救tau蛋白病小鼠模型的表型。这些结果表明，降低总tau蛋白水平是减轻tau蛋白相关神经退行性变的有效策略，并揭示Nuak1是tau蛋白病的一个新的治疗切入点。
