Mechanistic insight into female predominance in Alzheimer’s disease based on aberrant protein S-nitrosylation of C3
| Autor: | Hongmei Yang, Chang-ki Oh, Haitham Amal, John S. Wishnok, Sarah Lewis, Emily Schahrer, Dorit Trudler, Tomohiro Nakamura, Steven R. Tannenbaum, Stuart A. Lipton |
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| Rok vydání: | 2022 |
| Předmět: |
Male
Aging Multidisciplinary Post-Translational Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Proteins Brain Neurodegenerative Alzheimer's Disease Brain Disorders Alzheimer Disease Neurological Synapses Acquired Cognitive Impairment 2.1 Biological and endogenous factors Humans Dementia Female Aetiology Protein Processing Post-Translational Protein Processing |
| Zdroj: | Science advances, vol 8, iss 50 |
| ISSN: | 2375-2548 |
| DOI: | 10.1126/sciadv.ade0764 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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