The high-resolution mass spectrometry study of the protein composition of amyloid-like urine aggregates associated with preeclampsia

Sergeeva, V. A.; Zakharova, Natalia V.; Бугрова, А. Е.; Стародубцева, Н. Л.; Indeykina, Maria I.; Kononikhin, Alexey; Frankevich, Vladimir; Nikolaev, Eugene

doi:10.1177/1469066719860076

Cited by 13 publications

(18 citation statements)

References 15 publications

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“…One such approach could be based on MS-based identification of a unique urine proteomic fingerprint predicting PE. Such a protein profile includes alpha-1 antitrypsin, albumin, IgG k-free light chains, ceruloplasmin, and interferon-inducible protein 6-16 [99], later these data were supplemented by a-1-antitrypsin, complement 3, haptoglobin, and trypstatin [144]. This could be complemented by detection of increased TTR levels in body fluids [71].…”

Section: New Approaches To Pe Diagnosticsmentioning

confidence: 99%

Protein Misfolding during Pregnancy: New Approaches to Preeclampsia Diagnostics

Gerasimova

Fedotov

Kachkin

et al. 2019

IJMS

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Preeclampsia (PE) is a multisystem heterogeneous complication of pregnancy remaining a leading cause of maternal and perinatal morbidity and mortality over the world. PE has a large spectrum of clinical features and symptoms, which make diagnosis challenging. Despite a long period of studying, PE etiology is still unclear and there are no reliable rapid tests for early diagnosis of this disease. During the last decade, it was shown that proteins misfolding and aggregation are associated with PE. Several proteins, including amyloid beta peptide, transthyretin, alpha-1 antitrypsin, albumin, IgG k-free light chains, and ceruloplasmin are dysregulated in PE, resulting in toxic deposition of amyloid-like aggregates in the placenta and body fluids. It is also possible that aggregated proteins induce defective trophoblast invasion, placental ischemia, ER stress, and promote PE manifestation. The fact that protein aggregation is an emerging biomarker of PE provides an opportunity to develop new diagnostic approaches based on amyloids special features, such as Congo red (CR) staining and thioflavin T (ThT) enhanced fluorescence.

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Section: New Approaches To Pe Diagnosticsmentioning

confidence: 99%

Protein Misfolding during Pregnancy: New Approaches to Preeclampsia Diagnostics

Gerasimova

Fedotov

Kachkin

et al. 2019

IJMS

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“…The ability of these peptides in preeclamptic urine to bind the amyloidophilc dye Congo Red was successfully applied for clinical practice [15]. In the presence of Congo red azo-dye, the amyloid-like structures aggregate in urine [16]. It was shown that peptides of b-sheets, α1-antitrypsin (SERPINA1), complement 3, haptoglobin, ceruloplasmin, and trypstatin are most likely targets for Congo red binding [16].…”

Section: Introductionmentioning

confidence: 99%

“…In the presence of Congo red azo-dye, the amyloid-like structures aggregate in urine [16]. It was shown that peptides of b-sheets, α1-antitrypsin (SERPINA1), complement 3, haptoglobin, ceruloplasmin, and trypstatin are most likely targets for Congo red binding [16]. A no-invasive Congo Red Dot Paper Test for rapid identification of PE was also presented [17].…”

Section: Introductionmentioning

confidence: 99%

“…A no-invasive Congo Red Dot Paper Test for rapid identification of PE was also presented [17]. α1-antitrypsin is one of the most promising peptide markers of PE that have significantly higher aggregation capacity [16,18,19]. SERPINA1 is an abundant plasma protein primarily expressed in liver and involved in serine proteases inhibition, primarily neutrophil elastase.…”

Section: Introductionmentioning

confidence: 99%

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SERPINA1 Peptides in Urine as A Potential Marker of Preeclampsia Severity

Стародубцева

Nizyaeva

Baev

et al. 2020

IJMS

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Preeclampsia (PE) is a multisystem disorder associated with pregnancy and its frequency varies from 5 to 20 percent of pregnancies. Although a number of preeclampsia studies have been carried out, there is no consensus about disease etiology and pathogenesis so far. Peptides of SERPINA1 (α1-antitrypsin) in urine remain one of the most promising peptide markers of PE. In this study the diagnostic potential of urinary α1-antitrypsin peptides in PE was evaluated. The urinary peptidome composition of 79 pregnant women with preeclampsia (PE), chronic arterial hypertension (CAH), and a control group was investigated. Mann–Whitney U-test (p < 0.05) revealed seven PE specific SERPINA1 peptides demonstrating 52% sensitivity and 100% specificity. SERPINA1 in urine has been associated with the most severe forms of preeclampsia (p = 0.014), in terms of systolic hypertension (p = 0.01) and proteinuria (p = 0.006). According to Spearman correlation analysis, the normalized intensity of SERPINA1 urinary peptides has a similar diagnostic pattern with known diagnostic PE markers, such as sFLT/PLGF. SERPINA1 peptides were not urinary excreted in superimposed PE (PE with CAH), which is a milder form of PE. An increase in expression of SERPINA1 in the structural elements of the placenta during preeclampsia reflects a protective mechanism against hypoxia. Increased synthesis of SERPINA1 in the trophoblast leads to protein accumulation in fibrinoid deposits. It may block syncytial knots and placenta villi, decreasing trophoblast invasion. Excretion of PE specific SERPINA1 peptides is associated with syncytiotrophoblast membrane destruction degradation and increased SERPINA1 staining. It confirms that the placenta could be the origin of SERPINA1 peptides in urine. Significant correlation (p < 0.05) of SERPINA1 expression in syncytiotrophoblast membrane and cytoplasm with the main clinical parameters of severe PE proves the role of SERPINA1 in PE pathogenesis. Estimation of SERPINA1 peptides in urine can be used as a diagnostic test of the severity of the condition to determine further treatment, particularly the need for urgent surgical delivery.

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“…Liquid chromatography tandem-mass spectroscopy (LC-MS/MS) has been demonstrated as a very accurate, sensitive, rapid, and high-throughput analytical technique for identification, characterization, and quantitation of peptides and proteins. [1][2][3] Mass spectra of peptides acquired by LC-MS/MS usually contain a wealth of useful information about the protonated peptides and the related fragment ions, which can be utilized to deduce the chemical structures of the fragment ions, to decipher the peptide sequences, and to figure out the presence of the post-translational modifications. 2 Mass peak patterns of peptide/protein ions are known to be significantly dependent upon their sequences and gas-phase basicity of the amino acid residues.…”

Section: Introductionmentioning

confidence: 99%

Insight into nucleophilic fragmentation mechanisms by glutamic acid side chain in singly protonated glutathione and related peptidyl ions

Fan

Wang

Liu

et al. 2019

Eur J Mass Spectrom (Chichester)

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Fragmentation mechanisms of the singly protonated glutathione ( γ-ECG) and its synthetic analogue peptides (ECG and PPECG) have been investigated by liquid chromatography tandem-mass spectrometry and theoretical calculations. In the mass spectra, similar fragmentation patterns were observed for γ-ECG and ECG, but a completely different one was found in the case of PPECG. The E–C amide bond cleavage is the predominant pathway for the fragmentation of γ-ECG and ECG, whereas the additional N-terminal prolyl residues in PPECG significantly suppress the E–C amide bond cleavage. Theoretical calculations reveal that the fragmentation efficiencies of the E–C bonds in the protonated γ-ECG and ECG are much higher than that in the protonated PPECG, being attributed to their lower barriers of the potential energy; clearly the introduction of two prolyl residues can increase substantially the potential energy barrier. In the proposed mechanism, the protonated E–C amide bonds in the three peptides are first weakened followed by a nucleophilic addition by the glutamyl carboxyl oxygen atom in side chain, leading to the breaking of the E–C amide bonds. However, the processes of E–C bond fragmentation for three protonated analogs were not collaborative. Protonated amide bonds first fragment, then the nucleophilic addition by the side chain of glutamyl carboxyl oxygen atom takes places. On the other hand, the prolyl residues in PPECG can largely diminish the nucleophilic addition, resulting in a much lower efficiency of its E–C amide bond breaking. Distance analysis indicates that breaking the E–C amide bonds in the protonated γ-ECG, ECG, and PPECG ions could not occur without the assistance from the nucleophilic attack, highlighting an asynchronous collaborative process in the bond breakings.

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The high-resolution mass spectrometry study of the protein composition of amyloid-like urine aggregates associated with preeclampsia

Cited by 13 publications

References 15 publications

Protein Misfolding during Pregnancy: New Approaches to Preeclampsia Diagnostics

Protein Misfolding during Pregnancy: New Approaches to Preeclampsia Diagnostics

SERPINA1 Peptides in Urine as A Potential Marker of Preeclampsia Severity

Insight into nucleophilic fragmentation mechanisms by glutamic acid side chain in singly protonated glutathione and related peptidyl ions

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