An integrative systems-biology approach defines mechanisms of Alzheimer’s disease neurodegeneration
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 mea...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59654-w |
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| author | 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 Ernest Fraenkel |
| author_facet | 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 Ernest Fraenkel |
| author_sort | Matthew J. Leventhal |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-04b4a1ed664646868ab0f4a12f034fa1 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-04b4a1ed664646868ab0f4a12f034fa12025-08-20T02:29:45ZengNature PortfolioNature Communications2041-17232025-05-0116112110.1038/s41467-025-59654-wAn integrative systems-biology approach defines mechanisms of Alzheimer’s disease neurodegenerationMatthew J. Leventhal0Camila A. Zanella1Byunguk Kang2Jiajie Peng3David Gritsch4Zhixiang Liao5Hassan Bukhari6Tao Wang7Ping-Chieh Pao8Serwah Danquah9Joseph Benetatos10Ralda Nehme11Samouil Farhi12Li-Huei Tsai13Xianjun Dong14Clemens R. Scherzer15Mel B. Feany16Ernest Fraenkel17MIT Ph.D. Program in Computational and Systems BiologyDepartment of Pathology, Brigham and Women’s Hospital and Harvard Medical SchoolDepartment of Biological Engineering, Massachusetts Institute of TechnologyPrecision Neurology Program, Brigham and Women’s Hospital and Harvard Medical schoolPrecision Neurology Program, Brigham and Women’s Hospital and Harvard Medical schoolPrecision Neurology Program, Brigham and Women’s Hospital and Harvard Medical schoolDepartment of Pathology, Brigham and Women’s Hospital and Harvard Medical SchoolPrecision Neurology Program, Brigham and Women’s Hospital and Harvard Medical schoolPicower Institute for Learning and Memory, Massachusetts Institute of Technology, CambridgeSpatial Technology Platform, Broad Institute of Harvard and MITDepartment of Biological Engineering, Massachusetts Institute of TechnologySpatial Technology Platform, Broad Institute of Harvard and MITSpatial Technology Platform, Broad Institute of Harvard and MITBroad Institute of Harvard and MITPrecision Neurology Program, Brigham and Women’s Hospital and Harvard Medical schoolPrecision Neurology Program, Brigham and Women’s Hospital and Harvard Medical schoolDepartment of Pathology, Brigham and Women’s Hospital and Harvard Medical SchoolMIT Ph.D. Program in Computational and Systems BiologyAbstract 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.https://doi.org/10.1038/s41467-025-59654-w |
| spellingShingle | 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 Ernest Fraenkel An integrative systems-biology approach defines mechanisms of Alzheimer’s disease neurodegeneration Nature Communications |
| title | An integrative systems-biology approach defines mechanisms of Alzheimer’s disease neurodegeneration |
| title_full | An integrative systems-biology approach defines mechanisms of Alzheimer’s disease neurodegeneration |
| title_fullStr | An integrative systems-biology approach defines mechanisms of Alzheimer’s disease neurodegeneration |
| title_full_unstemmed | An integrative systems-biology approach defines mechanisms of Alzheimer’s disease neurodegeneration |
| title_short | An integrative systems-biology approach defines mechanisms of Alzheimer’s disease neurodegeneration |
| title_sort | integrative systems biology approach defines mechanisms of alzheimer s disease neurodegeneration |
| url | https://doi.org/10.1038/s41467-025-59654-w |
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