Work

Mechanistic insight into female predominance in Alzheimer’s disease based on aberrant protein S-nitrosylation of C3

Year: 2022

Type: article

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.

Source: Science Advances

DOI: 10.1126/sciadv.ade0764

Authors: Hongmei Yang, Chang-ki Oh, Haitham Amal, John S. Wishnok, Sarah Lewis, Emily Schahrer, Dorit Trudler, Tomohiro Nakamura, Steven R. Tannenbaum, Stuart A. Lipton

Institutions: Changchun University of Chinese Medicine, Massachusetts Institute of Technology, Scripps Research Institute, Hebrew University of Jerusalem, University of California San Diego

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Cellular and Molecular Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,500

Funders: Supernus Pharmaceuticals, Adamas Pharmaceuticals, National Institutes of Health, National Institute on Aging, National Institute on Drug Abuse, National Institute of Neurological Disorders and Stroke

Awards: Omics Analyses of HIV and Substance Use Disorder, Identification and Verification of S-Nitrosylated Proteins in Bodily Fluids as Biomarkers for Parkinson's Disease and Lewy Body Dementia, Novel Proteomics Approach to HIV-Associated Neurocognitive Disorder & Drug Abuse, S-Nitrosylation-Dependent Pathological Spread of Abnormal Proteins in Frontotemporal Dementia and Lewy Body Dementia, Dynamic Interactions of the S-Nitrosoproteome in Type 2 Diabetes/Metabolic Syndrome and Alzheimer’s Disease, Neuroprotective Mechanisms of S-Nitrosylated ApoE2 in Aging and Alzheimer's Disease, Pro-Electrophilic Drugs PEDs for Alzheimer's Disease, S-Nitrosylation-Induced Posttranslational Modification and Aberrant Cell Signaling in Sporadic Alzheimer's Disease, Crosstalk between innate-immunity human microglia and adaptive-immunity Tregs in Alzheimer's disease, Leadership in AD/ADRD Drug Discovery

OpenAlex ID: W4311441725

FWCI: 5.869

Cites: 96

Cited by: 73

Related to: 10