TY - JOUR
T1 - Mechanistic insight into female predominance in Alzheimer's disease based on aberrant protein Snitrosylation of C3
AU - Yang, Hongmei
AU - Oh, Chang Ki
AU - Amal, Haitham
AU - Wishnok, John S.
AU - Lewis, Sarah
AU - Schahrer, Emily
AU - Trudler, Dorit
AU - Nakamura, Tomohiro
AU - Tannenbaum, Steven R.
AU - Lipton, Stuart A.
N1 - Publisher Copyright:
© 2022 The Authors.
PY - 2022/12/14
Y1 - 2022/12/14
N2 - 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 (SNOTRAP) 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.
AB - 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 (SNOTRAP) 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.
UR - http://www.scopus.com/inward/record.url?scp=85144187061&partnerID=8YFLogxK
U2 - 10.1126/sciadv.ade0764
DO - 10.1126/sciadv.ade0764
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C2 - 36516243
AN - SCOPUS:85144187061
SN - 2375-2548
VL - 8
JO - Science advances
JF - Science advances
IS - 50
M1 - ade0764
ER -