An integrative systems-biology approach defines mechanisms of Alzheimer’s disease neurodegeneration
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.
Authors
- Matthew Leventhal (ORCID: https://orcid.org/0000-0002-5995-5202)
- Mel Β. Feany (ORCID: https://orcid.org/0000-0003-0315-7970)
- Clemens R. Scherzer (ORCID: https://orcid.org/0000-0002-0567-9193)
- David Gritsch
- Ralda Nehme (ORCID: https://orcid.org/0000-0001-7215-3311)
- Li‐Huei Tsai (ORCID: https://orcid.org/0000-0003-1262-0592)
- Ernest Fraenkel (ORCID: https://orcid.org/0000-0001-9249-8181)
- Ping‐Chieh Pao (ORCID: https://orcid.org/0000-0001-6788-7185)
- Joseph Benetatos (ORCID: https://orcid.org/0000-0001-8211-5642)
- Hassan Bukhari (ORCID: https://orcid.org/0000-0003-3328-8234)
- Xianjun Dong (ORCID: https://orcid.org/0000-0002-8052-9320)
- Samouil L. Farhi (ORCID: https://orcid.org/0000-0003-1359-4568)
- Jiajie Peng (ORCID: https://orcid.org/0000-0002-3857-7927)
- Zhixiang Liao (ORCID: https://orcid.org/0000-0001-7014-5465)
- Camila A. Zanella (ORCID: https://orcid.org/0000-0002-2448-5765)
- Serwah Danquah
- Tao Wang (ORCID: https://orcid.org/0000-0002-5728-6463)
- Byunguk Kang
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Northwestern Polytechnical University (CN)
- Institute of Cognitive and Brain Sciences (US)
- IIT@MIT (US)
- Massachusetts Institute of Technology (US)
- University of Aden (YE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-20
- DOI
- https://doi.org/10.1038/s41467-025-59654-w
- Citations
- 12
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 13.97
Funders
- Rush University
- National Institutes of Health
- National Institute on Aging