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

Autor:	Leventhal MJ; MIT Ph.D. Program in Computational and Systems Biology, Cambridge, MA, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.; Broad Institute of Harvard and MIT, Cambridge, MA, USA., Zanella CA; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Kang B; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.; Spatial Technology Platform, Broad Institute of Harvard and MIT, Cambridge, MA USA., Peng J; Precision Neurology Program, Brigham and Women's Hospital and Harvard Medical school, Boston, MA, USA.; APDA Center for Advanced Parkinson's Disease Research, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Gritsch D; Precision Neurology Program, Brigham and Women's Hospital and Harvard Medical school, Boston, MA, USA.; APDA Center for Advanced Parkinson's Disease Research, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Liao Z; Precision Neurology Program, Brigham and Women's Hospital and Harvard Medical school, Boston, MA, USA.; APDA Center for Advanced Parkinson's Disease Research, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Bukhari H; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Wang T; Precision Neurology Program, Brigham and Women's Hospital and Harvard Medical school, Boston, MA, USA.; APDA Center for Advanced Parkinson's Disease Research, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Present address: School of Computer Science, Northwestern Polytechnical University, Xi'an, China., Pao PC; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA., Danquah S; Spatial Technology Platform, Broad Institute of Harvard and MIT, Cambridge, MA USA.; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA., Benetatos J; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Nehme R; Spatial Technology Platform, Broad Institute of Harvard and MIT, Cambridge, MA USA.; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA., Farhi S; Spatial Technology Platform, Broad Institute of Harvard and MIT, Cambridge, MA USA., Tsai LH; Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA., Dong X; Precision Neurology Program, Brigham and Women's Hospital and Harvard Medical school, Boston, MA, USA.; APDA Center for Advanced Parkinson's Disease Research, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Scherzer CR; Precision Neurology Program, Brigham and Women's Hospital and Harvard Medical school, Boston, MA, USA.; APDA Center for Advanced Parkinson's Disease Research, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Present address: Stephen and Denise Adams Center of Yale School of Medicine, CT, USA., Feany MB; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Fraenkel E; MIT Ph.D. Program in Computational and Systems Biology, Cambridge, MA, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.; Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Lead contact.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 09. Date of Electronic Publication: 2024 Oct 09.
DOI:	10.1101/2024.03.17.585262
Abstrakt:	Despite years of intense investigation, the mechanisms underlying neuronal death in Alzheimer's disease, the most common neurodegenerative disorder, remain incompletely understood. To define relevant pathways, we integrated the results of an unbiased, genome-scale forward genetic screen for age-associated neurodegeneration in Drosophila with human and Drosophila Alzheimer's disease-associated multi-omics. We measured proteomics, phosphoproteomics, and metabolomics in Drosophila models of Alzheimer's disease and identified Alzheimer's disease human genetic variants that modify expression in disease-vulnerable neurons. We used a network optimization approach to integrate these data with previously published Alzheimer's disease multi-omic data. We computationally predicted and experimentally demonstrated how HNRNPA2B1 and MEPCE enhance tau-mediated neurotoxicity. Furthermore, we demonstrated that the screen hits CSNK2A1 and NOTCH1 regulate DNA damage in Drosophila and human iPSC-derived neural progenitor cells. Our work identifies candidate pathways that could be targeted to ameliorate neurodegeneration in Alzheimer's disease. Competing Interests: Competing interests The authors declare no competing financial interests.
Databáze:	MEDLINE
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