@article{4cf646b83dd149359105ec896180e2bd,
title = "Chlorpyrifos oxon crosslinking of amyloid beta 42 peptides is a new route for generation of self-aggregating amyloidogenic oligomers that promote Alzheimer's disease",
abstract = "Epidemiological evidence suggests that people chronically exposed to organophosphorus pesticides are at increased risk of neurodegenerative disease. Covalently linked amyloid beta dimers have been isolated from the brains of Alzheimer's patients. The toxic forms of amyloid beta are amyloid dimers that spontaneously oligomerize. In the present report we treated recombinant and synthetic amyloid beta (1–42) with 1 mM chlorpyrifos oxon or 1 mM paraoxon. The trypsin-digested samples were analyzed by liquid chromatography tandem mass spectrometry on an Orbitrap Fusion Lumos mass spectrometer. Data were searched with Protein Prospector software. We found two new types of crosslinks in amyloid dimers. An isopeptide Asp-Asp link occurred between the N-terminal amine of Asp 1 in one peptide and the beta carboxyl group of Asp 1 in another peptide. An Asp-Arg link occurred between the guanidino group of Arg 5 in one peptide and the beta carboxyl group of Asp 1 in another peptide. These results show that the active metabolites of the pesticides chlorpyrifos and parathion catalyze the crosslinking of amyloid beta (1–42) into toxic dimers. It was concluded that the increased risk of neurodegenerative disease in people exposed to organophosphorus pesticides could be explained by the crosslinking activity of these chemicals. Data are available via ProteomeXchange with identifier PXD034163.",
keywords = "Amyloid beta, Chlorpyrifos oxon, Crosslinks, Isopeptide",
author = "Seda Onder and Kevser Biberoglu and Ozden Tacal and Schopfer, {Lawrence M.}",
note = "Funding Information: This work was supported by the Fred & Pamela Buffet Cancer Center Support Grant [grant number P30CA036727], by the National Institutes of Health grant [grant number 1R21ES030132-01A1], and by the TUBITAK grant [grant number SBAG-318S259] (to SO).Mass spectrometry data were obtained by the Mass Spectrometry and Proteomics Core Facility at the University of Nebraska Medical Center, which is supported by state funds from the Nebraska Research Initiative. Protein Prospector programs are available at no cost https://prospector.ucsf.edu [prospector.ucsf.edu] accessed Jan2022. They were developed in the University of California San Francisco Mass Spectrometry Facility, directed by Dr. Alma Burlingame, funded by the NIH National Institute for General Medical Sciences. The Proteomics Toolkit http://db.systemsbiology.net:8080/proteomicsToolkit/, accessed July 2021 was used to assist in sequence determination. Proteome Discoverer (Thermo Scientific, Waltham MA), and Xcalibur Qual Browser (Thermo Scientific, Waltham MA) were used to identify ions in MS/MS spectra. The mass spectrometry proteomics data have been deposited to ProteomeXchange Consortium [27] via the PRIDE [28] partner repository with the dataset identifier PXD034163. Funding Information: Mass spectrometry data were obtained by the Mass Spectrometry and Proteomics Core Facility at the University of Nebraska Medical Center, which is supported by state funds from the Nebraska Research Initiative . Protein Prospector programs are available at no cost https://prospector.ucsf.edu [prospector.ucsf.edu] accessed Jan2022. They were developed in the University of California San Francisco Mass Spectrometry Facility , directed by Dr. Alma Burlingame, funded by the NIH National Institute for General Medical Sciences . The Proteomics Toolkit http://db.systemsbiology.net:8080/proteomicsToolkit/ , accessed July 2021 was used to assist in sequence determination. Proteome Discoverer (Thermo Scientific, Waltham MA), and Xcalibur Qual Browser (Thermo Scientific, Waltham MA) were used to identify ions in MS/MS spectra. Funding Information: This work was supported by the Fred & Pamela Buffet Cancer Center Support Grant [grant number P30CA036727 ], by the National Institutes of Health grant [grant number 1R21ES030132-01A1 ], and by the TUBITAK grant [grant number SBAG-318S259 ] (to SO). Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = aug,
day = "25",
doi = "10.1016/j.cbi.2022.110029",
language = "English (US)",
volume = "363",
journal = "Chemico-Biological Interactions",
issn = "0009-2797",
publisher = "Elsevier Ireland Ltd",
}