Leventhal Matthew J, Zanella Camila A, Kang Byunguk, Peng Jiajie, Gritsch David, Liao Zhixiang, Bukhari Hassan, Wang Tao, Pao Ping-Chieh, Danquah Serwah, Benetatos Joseph, Nehme Ralda, Farhi Samouil, Tsai Li-Huei, Dong Xianjun, Scherzer Clemens R, Feany Mel B, Fraenkel Ernest
MIT Ph.D. Program in Computational and Systems Biology, Cambridge, MA, USA.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Nat Commun. 2025 May 20;16(1):4441. doi: 10.1038/s41467-025-59654-w.
Despite years of intense investigation, the mechanisms underlying neuronal death in Alzheimer's disease, remain incompletely understood. To define relevant pathways, we conducted an unbiased, genome-scale forward genetic screen for age-associated neurodegeneration in Drosophila. We also measured proteomics, phosphoproteomics, and metabolomics in Drosophila models of Alzheimer's disease and identified Alzheimer's genetic variants that modify gene expression in disease-vulnerable neurons in humans. We then used a network model to integrate these data with previously published Alzheimer's disease proteomics, lipidomics and genomics. Here, we computationally predict and experimentally confirm how HNRNPA2B1 and MEPCE enhance toxicity of the tau protein, a pathological feature of Alzheimer's disease. Furthermore, we demonstrated that the screen hits CSNK2A1 and NOTCH1 regulate DNA damage in Drosophila and human stem cell-derived neural progenitor cells. Our study identifies candidate pathways that could be targeted to ameliorate neurodegeneration in Alzheimer's disease.
尽管经过多年深入研究，但阿尔茨海默病中神经元死亡的潜在机制仍未完全明了。为了确定相关途径，我们针对果蝇中与年龄相关的神经退行性变进行了一项无偏向性的全基因组正向遗传筛选。我们还对阿尔茨海默病果蝇模型进行了蛋白质组学、磷酸蛋白质组学和代谢组学测量，并鉴定出可改变人类疾病易损神经元中基因表达的阿尔茨海默病遗传变异。然后，我们使用网络模型将这些数据与先前发表的阿尔茨海默病蛋白质组学、脂质组学和基因组学数据整合起来。在此，我们通过计算预测并实验证实了HNRNPA2B1和MEPCE如何增强tau蛋白的毒性，tau蛋白毒性是阿尔茨海默病的一个病理特征。此外，我们证明筛选出的CSNK2A1和NOTCH1在果蝇和人类干细胞衍生的神经祖细胞中调节DNA损伤。我们的研究确定了可作为靶点以改善阿尔茨海默病神经退行性变的候选途径。
