An integrative systems-biology approach defines mechanisms of Alzheimer’s disease neurodegeneration

Matthew J. Leventhal, Camila A. Zanella, Byunguk Kang, Jiajie Peng, David Gritsch, Zhixiang Liao, Hassan Bukhari, Tao Wang, Ping-Chieh Pao, Serwah Danquah, Joseph Benetatos, Ralda Nehme, Samouil Farhi, Li-Huei Tsai, Xianjun Dong, Clemens R. Scherzer, Mel B. Feany and Ernest Fraenkel ()
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Matthew J. Leventhal: MIT Ph.D. Program in Computational and Systems Biology
Camila A. Zanella: Brigham and Women’s Hospital and Harvard Medical School
Byunguk Kang: Massachusetts Institute of Technology
Jiajie Peng: Brigham and Women’s Hospital and Harvard Medical school
David Gritsch: Brigham and Women’s Hospital and Harvard Medical school
Zhixiang Liao: Brigham and Women’s Hospital and Harvard Medical school
Hassan Bukhari: Brigham and Women’s Hospital and Harvard Medical School
Tao Wang: Brigham and Women’s Hospital and Harvard Medical school
Ping-Chieh Pao: Cambridge
Serwah Danquah: Broad Institute of Harvard and MIT
Joseph Benetatos: Massachusetts Institute of Technology
Ralda Nehme: Broad Institute of Harvard and MIT
Samouil Farhi: Broad Institute of Harvard and MIT
Li-Huei Tsai: Broad Institute of Harvard and MIT
Xianjun Dong: Brigham and Women’s Hospital and Harvard Medical school
Clemens R. Scherzer: Brigham and Women’s Hospital and Harvard Medical school
Mel B. Feany: Brigham and Women’s Hospital and Harvard Medical School
Ernest Fraenkel: MIT Ph.D. Program in Computational and Systems Biology

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59654-w

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