Mechanistic insight into female predominance in Alzheimer’s disease based on aberrant protein S-nitrosylation of C3
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sciadv.ade0764.pdf
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Published version
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1.82 MB
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Author(s)
Yang, Hongmei
Oh, Chang-ki
Amal, Haitham
Wishnok, John S
Lewis, Sarah
Schahrer, Emily
Trudler, Dorit
Nakamura, Tomohiro
Tannenbaum, Steven R
Lipton, Stuart A
Date Issued
December 14, 2022
Journal
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Yang, Hongmei, Oh, Chang-ki, Amal, Haitham, Wishnok, John S, Lewis, Sarah et al. 2022. "Mechanistic insight into female predominance in Alzheimer’s disease based on aberrant protein S-nitrosylation of C3." Science Advances, 8 (50).
Version
Final published version
Abstract
Protein S-nitros(yl)ation (SNO) is a posttranslational modification involved in diverse processes in health and disease and can contribute to synaptic damage in Alzheimer’s disease (AD). To identify SNO proteins in AD brains, we used triaryl phosphine ( SNO TRAP) combined with mass spectrometry (MS). We detected 1449 SNO proteins with 2809 SNO sites, representing a wide range of S-nitrosylated proteins in 40 postmortem AD and non-AD human brains from patients of both sexes. Integrative protein ranking revealed the top 10 increased SNO proteins, including complement component 3 (C3), p62 (SQSTM1), and phospholipase D3. Increased levels of S-nitrosylated C3 were present in female over male AD brains. Mechanistically, we show that formation of SNO-C3 is dependent on falling β-estradiol levels, leading to increased synaptic phagocytosis and thus synapse loss and consequent cognitive decline. Collectively, we demonstrate robust alterations in the S-nitrosoproteome that contribute to AD pathogenesis in a sex-dependent manner.
Protein S-nitros(yl)ation (SNO) is a posttranslational modification involved in diverse processes in health and disease and can contribute to synaptic damage in Alzheimer’s disease (AD). To identify SNO proteins in AD brains, we used triaryl phosphine ( SNO TRAP) combined with mass spectrometry (MS). We detected 1449 SNO proteins with 2809 SNO sites, representing a wide range of S-nitrosylated proteins in 40 postmortem AD and non-AD human brains from patients of both sexes. Integrative protein ranking revealed the top 10 increased SNO proteins, including complement component 3 (C3), p62 (SQSTM1), and phospholipase D3. Increased levels of S-nitrosylated C3 were present in female over male AD brains. Mechanistically, we show that formation of SNO-C3 is dependent on falling β-estradiol levels, leading to increased synaptic phagocytosis and thus synapse loss and consequent cognitive decline. Collectively, we demonstrate robust alterations in the S-nitrosoproteome that contribute to AD pathogenesis in a sex-dependent manner.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
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DOI of Published Version
https://doi.org/10.1126/sciadv.ade0764
