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Multi-targeted organometallic ruthenium(II)-arene anticancer complexes bearing inhibitors of poly(ADP-ribose) polymerase-1: A strategy to improve cytotoxicity.
Proteomic profile of serum from patients
with schizophrenia spectrum disorders
Elena Dmitrieva1 , Liudmila Smirnova1 , Alexander Seregin1 , Victor Zgoda2 ,
Arkadij Semke1 and Svetlana Ivanova1
1
Laboratory of Molecular Genetics and Biochemistry, Mental Health Research Institute, Tomsk National
Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia
2
Laboratory of Systems Biology, Institute of Biomedical Chemistry, Moscow, Russia
ABSTRACT
This article describes the most likely classes of proteins and molecular processes
that specifically characterize schizophrenic spectrum disorders such as simple and
paranoid schizophrenia, schizotypal disorder, and acute polymorphic psychotic
disorder (APPD). The identification of patients’ serum proteins was carried out
using mass spectrometry. For patients with paranoid schizophrenia, the proteins
responsible for translation and transcription are characteristic. A significant part of
the proteins of patients with simple schizophrenia regulate the cell’s main metabolic
and transport processes. These are proteins of the receptor system, vesicular transport,
and extracellular matrix, which mainly carry out catabolic processes. The proteins of
patients with schizotypal disorder mostly coincided with the classes of other patients,
apart from chaperone proteins, which were not found in other studied groups. These
proteins are mainly involved in anabolic processes. The main classes of proteins found in
patients with APPD are responsible for the metabolism of nucleic acids. Active apoptosis
processes were also revealed in these patients. These results from our basic knowledge
about the molecular mechanisms of the pathogenesis of these disorders.
Subjects Biochemistry, Computational Biology, Molecular Biology, Cognitive Disorders,
Submitted 19 May 2022
Accepted 27 July 2022
Published 30 August 2022
Corresponding author
Liudmila Smirnova,
lpsmirnova2016@gmail.com
Academic editor
Yuriy Orlov
Additional Information and
Declarations can be found on
page 17
DOI 10.7717/peerj.13907
Copyright
2022 Dmitrieva et al.
Distributed under
Creative Commons CC-BY 4.0
OPEN ACCESS
Psychiatry and Psychology
Keywords Schizophrenia, Schizotypal disorder, Proteomics, Mass spectrometry, System biology
INTRODUCTION
Schizophrenia and schizophrenia spectrum disorders are multifactorial diseases
characterized by delusions, hallucinations, affective flattening, and cognitive deficits
that lead to persistent impairment of social adaptation and working capacity in young
patients (Charlson et al., 2018; Marder & Cannon, 2019; Serafini et al., 2011). We suspect
that acute polymorphic psychotic disorder and schizotypal disorder, which we are studying,
may have identical pathological natures (Malhotra, Sahoo & Balachander, 2019; Lewine &
Hart, 2020; Driver et al., 2020). They are characterized by an acute beginning of psychotic
symptoms (duration less than two weeks) and are often connected with stress events and
with rapid reduction of symptoms. Although if we study the pathogenetic of schizotypal
disorder more deeply, we find that molecular hypotheses of schizophrenia’s origin, such
as the endocannabinoid, kynurenine and dysontogenic theories, may be quite useful. The
appearances of crossed pathogenetic sites of schizophrenia and schizotypal disorder onset
How to cite this article Dmitrieva E, Smirnova L, Seregin A, Zgoda V, Semke A, Ivanova S. 2022. Proteomic profile of serum from patients with schizophrenia spectrum disorders. PeerJ 10:e13907 http://doi.org/10.7717/peerj.13907
have been studied (Ma et al., 2016). The pathogenesis of acute polymorphic psychotic
disorder is connected with processes that are broken in schizophrenia patients. There are
significant results that prove the stress diathesis hypothesis. This postulates that acute
polymorphic psychotic disorder can manifest in persons with genetic vulnerabilities (Das
et al., 2001). Moreover, López-Díaz, Lara & Luis Fernández-González (2018) suggested that
patients with acute polymorphic psychotic disorder can have schizophrenia with their first
episode.
Schizotypal disorder is characterized by eccentric behavior, thought disorder, and effects
that resemble those seen in schizophrenia, but the severity of symptoms indicates no
definite and characteristic schizophrenic anomalies. It is thought that individuals with
schizotypal disorder share genetic and neurocognitive abnormalities with patients with
schizophrenia (Siever & Davis, 2004). Some studies offer information about the appearance
of non-specific symptoms in persons with schizotypal disorder. These symptoms may have
a mixed nature of manifestation, with both genetic and environmental causes (Tsuang
et al., 2002; Torgersen et al., 2002). Non-specificity in symptoms indicates that a single
biological basis can underly different phenotypes and different biological bases can result
in a single phenotype.
The main obstacle to developing highly effective treatment tactics is the lack of
diagnostic criteria based on up-to-date data on the etiology and pathogenesis of mental
disorders (Faiad et al., 2018). Currently, proteome studies provide the most information
about the biological functioning of the body.
There are very few studies in the literature on the comparative proteomic analysis of
different types of schizophrenic spectrum disorders. In addition, there are no articles
specifically devoted to comparing proteomes in patients with simple schizophrenia
and schizotypal disorder. It was only possible to discover a few early works on the
study of APPD. Biochemical studies have revealed metabolic changes in amino acid
pathways (Pepplinkhuizen et al., 2003) and increased levels of bilirubin in patients with
APPD compared to patients with schizophrenia (Bach, Kindler & Strik, 2010; Pillmann et
al., 2001).
In a recent study aimed at analyzing the genetic correlations between the blood plasma
proteome and mental disorders, a set of 15 plasma proteins was identified that showed
an association only with schizophrenia (Mahadevan et al., 2017). It is assumed that the
identification of proteome features in mental patients may be complicated by multilevel
interactions between changes caused by the pathological process and changes resulting from
drug therapy. The question of whether biological interpretations based only on genetic
information will reflect the fundamental genetic architecture of the most complex human
traits has not yet been resolved. The problem of creating a panel of markers for mental
disorders requires a systems biology approach (integration of genomic, transcriptomic and
proteomic data, metabolomics, gene networks, epigenetics and environmental factors),
where gene expression profiling is an important component of gene networks (Cheng et
al., 2020).
In this article, methods of systems biology, classes of proteins, and molecular processes
that specifically characterize disorders of the schizophrenia spectrum such as simple and
Dmitrieva et al. (2022), PeerJ, DOI 10.7717/peerj.13907
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paranoid schizophrenia, schizotypal disorder, and acute polymorphic psychotic disorder
will be analyzed.
MATERIALS & METHODS
The formation of patient groups for research and clinical verification of diagnoses was
performed in the Department of Endogenous Disorders of the Mental Health Research
Institute at the Tomsk National Research Medical Center of the Russian Academy of
Sciences.
The study was conducted according to the guidelines of the Declaration of Helsinki and
approved by the Ethical Committee of the Mental Health Research Institute No 151 from
14 March 2022 (No 151/1.2022).
The clinical verification of diagnoses was carried out by qualified psychiatrists according
to the clinical criteria approved by the International Classification of Diseases, 10th Revision
(ICD-10), for disorders of heading F2.
Criteria for inclusion of patients: male and female individuals aged 18 to 55 years; the
diagnosis determined by psychiatrists; the presence of a signed form of informed consent
to participate in the study.
Criteria for the inclusion of healthy individuals: conformity by gender and age with the
studied group of patients; the presence of a signed form of informed consent to participate
in the study.
Criteria for non-inclusion for all individuals: age under 18 and over 55 years; the presence
of acute or exacerbated chronic infections, inflammatory or autoimmune diseases at the
time of examination; acute infectious diseases less than four weeks before the start of the
study; use of medications and narcotic substances; the presence of comorbid mental and
neurological diseases in the patient; the presence of sexually transmitted diseases; refusal
to participate in the study.
Comparative proteomic analysis was carried out on a sample of 35 people (18 women, 17
men). As part of the study, the following study groups were formed —simple and paranoid
schizophrenia, schizotypal disorder, and acute polymorphic psychotic disorder (APPD).
Patients in the schizotypal disorder and APPD groups had not previously taken drug
therapy, and patients with schizophrenia took a break from antipsychotic therapy for 2–3
months to a year.
The median age of all individuals included in the survey and the median duration
of the illness for individuals with schizophrenia spectrum disorders are presented in
Table 1. When the groups were compared pairwise, significant differences were identified
between the ages of the control group and the schizotypal disorder (p = 0,004) and acute
polymorphic psychotic disorder (p = 0,018) groups. When we compared the duration of
illness in the simple schizophrenia group with the paranoid schizophrenia (p = 0,04) and
APPD (p = 0,03) groups, significant differences were identified. Differences in sex and age
between other groups were not significant.
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Table 1 Characteristics of the individuals included in the study.
Group
Gender M/F
Age
(years)
Duration of illness (years)
Simple
schizophrenia
3/2
31.0 [25.5;40.5]
12.5 [6.5;17.00]
Paranoid
schizophrenia
6/6
30.5 [25.5;43.5]
3.0 [0.5;5.0]
Schizotypal disorder
3/2
19.0 [19.0;21.0]
2.5 [3.0;4.0]
Acute polymorphic psychotic disorder
2/3
24.0 [22.0;27.5]
0.03 [0.02;0.04]
Controls
3/8
39 [29;43]
—
Schizophrenia
Sample preparation
Blood was collected in test tubes (Becton Dickinson Vacutainer, Netherlands) containing
a clot activator. The blood was centrifuged to obtain serum. For 20 min at 2000×g using
the Digicen 21R centrifuge (Orto Alresa, Madrid, Spain). Aliquots of serum was stored at
−80 ◦ C.
Serum samples were diluted 3-fold with sodium–phosphate buffer (phosphate buffered
saline, PBS), centrifuged at 16,000 rpm for 1 min on a Centrifuge Z 36 HK centrifuge
(Hermle labortechnik Gmbh, Wehingen, Germany) at 4 ◦ C, and filtered through a
standard Filtropur S filter (Sarstedt, Nümbrecht, Germany) with a diameter of 22
µm. Affinity depletion of high-abundant proteins (albumin, IgG, antitrypsin, IgA,
transferrin, haptoglobin, fibrinogen, alpha2-macroglobulin, alpha1-acid glycoprotein,
IgM, apolipoprotein AI, apolipoprotein AII, complement C3 and transthyretin) from
samples were made on a chromatographic column Multiple Affinity Removal Column
Human-14, 4.6 ×100 mm (Agilent, USA), using a chromatograph from the company
ÄKTA pure (GE Healthcare, Chicago, IL, USA).q2 The purified protein mixture was
concentrated by ultrafiltration through Amicon Ultra−0.5 mL kDa centrifuge filters
(Merck Millipore, Molsheim, Alsace, France) in accordance with the protocol provided
by the manufacturer. Protein concentration was measured by absorbance at 280/260 nm
using an Epoch microplate spectrophotometer (BioTek, USA) with the software installed.
Sample preparation: One-dimensional Laemmli PAG electrophoresis.
Trypsinolysis
Electrophoretic separation (SDS-PAGE-based method) of serum proteins was carried out
on a 1 mm thick 16× 16 cm gel prepared with 12% acrylamide. A 20 µg portion of total
protein in a Laemmli sample buffer was loaded into a 10 mm well of the gel and separated
using a Protean II xi Cell (Bio-Rad, Hercules, CA, USA) device at 150–180 V. After protein
separation, gels were stained with Coomassie Brilliant Blue G250, then washed the color
in a solution of 70% ethanol for 2 h. Prior to trypsinolysis, the gel pieces were incubated
three times in 50% (v/v) acetonitrile and 100 mM ammonium bicarbonate (pH 8.9) for
20 min. Then the gel pieces were dried in a vacuum concentrator. In-gel trypsinolysis of the
proteins was carried out using Sequencing Grade Modified Trypsin (#V511A; Promega,
Madison, WI, USA). Trypsin was added to each sample at a concentration of 0.01–0.025
µg/mL. Samples were incubated with trypsin at 37 ◦ C for 18 h. The extraction of peptide
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mixtures from the gels was done with 50% acetonitrile in 5% formic acid, the procedure
was triplicated. The extracts were lyophilized and frozen.
Mass spectrometry analysis and protein identification
Mass spectrometric analysis was carried out in accordance with the previously described
protocols of our studies and those of our colleagues (Naryzhny et al., 2016; Smirnova et al.,
2019). The peptide samples obtained were analyzed using the Agilent HPLC system1100
Series (Agilent Technologies, Santa Clara, CA, USA) connected to LTQ Orbitrap Velos,
equipped with a nanoelectrospray ion source (Thermo Scientific, Waltham, MA, USA).
Peptide separations were carried out on an RP-HPLC Zorbax 300SB-C18 column (75 µm
inner diameter and 150 mm length; Agilent Technologies, Santa Clara, CA, USA) using a
linear gradient from 95% solvent A (water, 0.1% formic acid) and 5% solvent B (water,
0.1% formic acid, and 80% acetonitrile) to 60% solvent B over 85 min at a flow rate of 0.3
µL/min.
Mass spectra were acquired in the positive ion mode in a range of 300–1500 m/z with
a resolution of 30,000 (m/z = 400) for MS and in the range from 100 m/z to m/z value
determined by a charge state of the precursor at resolution 7,500 (m/z = 400) for MS/MS
scans. The maximum integration time was 50 ms and 110 ms for precursor and fragment
ions, correspondently. AGC target for precursor and fragment ions were set to 1*106 and
1*105, correspondently. An isolation intensity threshold of 5,000 counts was determined
for precursor’s selection and up to top 10 precursors were chosen for fragmentation with
high-energy collisional dissociation (HCD) at 35 eV. Precursors with a charge state of +1
and more than +5 were rejected and all measured precursors were dynamically excluded
from triggering of a subsequent MS/MS for 60 s (Naryzhny et al., 2016; Smirnova et al.,
2019).
Proteins were identified using the MASCOT software (http://www.matrixscience.com)
in the UniProtKB database, Homo sapiens taxon. The search parameters have been set:
the enzyme is trypsin, the tolerance for the monoisotopic peptide is ±10 ppm, the
MS/MS tolerance window was set to ±0.01 Da, and one missed cleavage was allowed.
Cysteine propionamide modification and oxidized methionine were chosen as variable
modifications. The criteria of positive identification were set as following: peptide and
protein FDR < 0.01, at least two matched peptides per protein, minimum protein score
more than 30.
Statistical and bioinformatics analysis
Statistical environment R was used to carry out statistical processing of the obtained results
(R Core Team, 2018). Statistical differences were determined by Fisher’s exact test with
Yates’s correction.
The Gene Ontology Database was used for the identification and analysis of biological
pathways (http://geneontology.org/) (Gene Ontology Consortium, 2021). The PANTHER
(Protein Analysis Through Evolutionary Relationships) tool was used to work with the
Gene Ontology Database (http://pantherdb.org/) (Mi et al., 2019).
Proteins were classified into three categories by GO annotation: biological processes,
regulation of biological processes, and molecular functions. For each category, a two-tailed
Dmitrieva et al. (2022), PeerJ, DOI 10.7717/peerj.13907
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Fisher’s exact test with FDR-controlling was used to measure the enrichment of differentially
abundant proteins for all identified proteins.
RESULTS
As a result of quantitative mass spectrometric analysis of a peptide mixture from purified
blood serum in the MS and MS/MS mode and subsequent identification of proteins using
the Mascot Version 2.1 software and the UniProtKB database, a total of 4,354 proteins were
identified for all groups. We identified 961 proteins in the control group, 1,440 proteins
in the paranoid schizophrenia group, 772 proteins in the simple schizophrenia group, 921
proteins in the schizotypal disorder group, and 260 proteins in the acute polymorphic
psychotic disorder group. The overlaps between proteins in all groups are presented a
Venn diagram in Fig. 1.
Subsequently, the results were subjected to statistical processing using Fisher’s exact test
with Yates’s correction in the statistical environment R. This statistical approach made it
possible to preserve the minor proteins in the blood serum in very low concentrations in
the analysis results.
After statistical processing of the data, highly significant differences were revealed
between the blood serum proteins of patients with schizophrenic spectrum disorders
and the control group (Table 2). The smallest number of highly significant differences
in the protein profiles were found in patients with acute polymorphic psychotic disorder
compared with healthy people.
At a later stage, a statistical evaluation of the differences in serum proteomes among the
studied groups of patients was carried out. Table 3 presents the results of an intergroup
comparison of proteomic profiles. Significant differences were revealed among all groups.
Thus, despite one nosological group, the studied mental disorders showed a high
specificity of proteomic profiles. Venn diagrams well reflect that there are few overlapping
proteins in the studied groups (Fig. 2). Further, this is also confirmed by statistical
analysis.
The most significant differences were found between the proteomic profiles of patients
with paranoid schizophrenia and schizotypal disorder (p = 3.20E−12), and the least were
found between patients with simple schizophrenia and schizotypal disorder (p = 0.016),
which reflected the similarity in the first case and the differences in clinical and pathogenetic
patterns in the second.
To further evaluate the differences in the proteomic profiles of the studied groups,
proteins that occurred only in patients with one disorder and not in healthy individuals
were selected. Unique protein spectra were formed by symmetric comparison of the
proteomic profiles of all five groups with the removal of common proteins. The number of
proteins in the paranoid schizophrenia group was 713, in the simple schizophrenia group
385 proteins, in the schizotypal disorder group 328 proteins, and in the acute polymorphic
psychotic disorder group 60 proteins.
Then, an analysis of the functional activity of proteins was carried out on the unique
protein spectra formed for each disorder. For each studied disorder, functional classes of
Dmitrieva et al. (2022), PeerJ, DOI 10.7717/peerj.13907
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Table 2 Differences between the proteomes of patients with schizophrenic spectrum disorders and
healthy people, revealed by Fisher’s test with Yates’s correction (p, level).
Group
Fisher’s test, p
Control/Paranoid schizophrenia
9.67E−09
Control/Simple schizophrenia
9.65E−05
Control/Schizotypal disorder
0.0006
Control/Acute polymorphic psychotic disorder
6.35E−27
Figure 1 Diagram of the distribution of identified proteins between experimental groups. (A) Paranoid schizophrenia. (B) Schizotypal disorder. (C) Simple schizophrenia. (D) Acute polymorphic psychotic
disorder. (E) Control group.
Full-size DOI: 10.7717/peerj.13907/fig-1
proteins were determined using the PANTHER TM Protein Class program (version 16.0,
from 1 December 2020). Table 4 shows the number of proteins belonging to a certain class
in each study group and indicates the level of significance of differences (according to the
PANTHER program). Statistical analysis was carried out with Fisher’s exact test with false
discovery rate-controlling.
During our research, when studying the distribution of proteins by class in different
disorders of the schizophrenia spectrum, interesting and unique results were obtained.
Thus, most of the proteins mediating translational and transcriptional processes were
Dmitrieva et al. (2022), PeerJ, DOI 10.7717/peerj.13907
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Table 3 Differences in proteomes among different groups of patients with schizophrenic spectrum
disorders identified using Fisher’s test with Yates’s correction (p, level).
Group
Fisher’s test, p
Paranoid schizophrenia/Simple schizophrenia
0.0008
Paranoid schizophrenia/Schizotypal disorder
3.20E−12
Paranoid schizophrenia/Acute polymorphic psychotic
disorder
0.006
Simple schizophrenia/Schizotypal disorder
0.016
Simple schizophrenia/Acute polymorphic psychotic
disorder
5.35E−09
Schizotypal disorder/Acute polymorphic psychotic disorder
2.06E−06
Figure 2 Diagram of the distribution of group-specific proteomic profiles between experimental
groups. (A) Paranoid schizophrenia. (B) Schizotypal disorder. (C) Simple schizophrenia. (D) Acute
polymorphic psychotic disorder.
Full-size DOI: 10.7717/peerj.13907/fig-2
found in patients with paranoid schizophrenia. For the group with simple schizophrenia,
the main number of proteins were related to the receptor apparatus, vesicular transport,
and extracellular matrix proteins. The proteins of patients with schizotypal disorder mostly
coincided with the classes of other groups of patients, except of chaperone proteins, which
were not found in any other disorder. The main class of proteins identified in patients with
an acute polymorphic psychotic disorder metabolized nucleic acids.
To further study the properties of protein profiles in each study group, the biological
processes carried out by the identified proteins were also determined using PANTHER
TM GO slim. The tables below show the biological processes characteristic of each studied
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Table 4 Protein classes were determined using the PANTHER program for each study group (Fisher’s exact test with FDR).
Protein class
Paranoid
schizophrenia
No*
P-value
No*
12
5.84E−03
63
3.8E−03
11
3.41E−02
4
4.69E−02
20
Extracellular matrix protein
Protein-binding activity modulator
Simple
schizophrenia
Vesicle coat protein
Nucleic acid metabolism protein
32
4.79E−02
Metabolite interconversion enzyme
101
2.64E−02
Protein modifying enzyme
Gene-specific transcriptional regulator
60
2.06E−02
Translational protein
83
2.55E−05
Transmembrane signal receptor
15
3.00E−03
Schizotypal
disorder
No*
P-value
1.11E−02
75
3.88E−02
5
3.12E−02
27
4.50E−02
12
4.22E−02
18
2.24E−02
4
2.04E−02
P-value
Transporter
Chromatin/chromatin-binding,
or -regulatory protein
25
1.07E−02
Cytoskeletal protein
83
3.11E−06
Chaperone
59
6.05E−03
23
4.32E−02
3
2.20E−02
Acute polymorphic
psychotic disorder
No*
P-value
12
4.68E−02
5
2.14E−02
4
1.03E−02
5
2.33E−02
2
1.9E−02
Notes.
*No, Number of proteins.
group of disorders. In addition data about processes for men and women are presented, in
which it is clear that the differences do not depend on gender (Table S1). In all groups, the
processes in men and women coincide in 50–60%.
In the group with paranoid schizophrenia, 713 proteins were involved in 105 bio-logical
processes combined into groups (Table 5). Biological processes characterizing significant
proteins in the blood serum of patients with paranoid schizophrenia (PANTHER).
In patients with paranoid schizophrenia, most of the identified proteins were associated
with the biosynthesis and assembly of macromolecular complexes, as well as subsequent
cell transport and the location of organelles inside the cell. A large group of proteins was
associated with the synthesis, functioning, and regulation of the actin cytoskeleton. Proteins
involved in various regulatory processes, in particular, the regulation of translation and
transcription processes, were identified.
In the group with simple schizophrenia, 385 proteins were involved in 50 biological
processes (Table 6).
A significant number of proteins in patients with simple schizophrenia regulated the
cell’s main metabolic and transport processes, and some proteins provided intercellular
communication. In contrast to the widely represented metabolic processes in the paranoid
schizophrenia group, the proteins of patients with simple schizophrenia mainly carried out
catabolism of macromolecules. Common to simple and paranoid schizophrenia were the
processes of organelle distribution within the cell and intracellular transport of molecules.
However, for the group with simple schizophrenia, most of the transport proteins mediated
the transfer of molecules and signals between cells. The processes included in the group of
vesicular transport were associated with exocytosis and secretion.
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Table 5 Biological processes characterizing significant proteins in the blood serum of patients with
paranoid schizophrenia (PANTHER).
Metabolic
processes
Cellular
processes
Regulation
of biological
processes
Groups of biological processes
Number of
processes
Process ID*
Cellular macromolecule
biosynthetic process
2
GO:0034645
Macromolecule metabolic
process
4
GO:0043170
Nucleic acid metabolic process
8
GO:0090304
Metabolism of nitrogenous
compounds
11
GO:0006807
Cell population proliferation
1
GO:0008283
Vacuole organization
1
GO:0007033
Intracellular transport
3
GO:0046907
Chromosome organization
4
GO:0051276
Actin cytoskeleton organization
5
GO:0030036
Cellular protein localization
5
GO:0034613
Ribosome biogenesis
6
GO:0042254
Cellular component assembly
7
GO:0022607
Cellular component organization
10
GO:0016043
Regulation of cellular amide
metabolic process
1
GO:0034248
Regulation of cellular
component size
2
GO:0032535
Intracellular signal transduction
2
GO:0035556
Regulation of RNA
metabolic process
2
GO:0051252
Regulation of chromatin
organization
2
GO:1902275
Regulation of programmed
cell death
2
GO:0043067
Regulation of protein
metabolic process
4
GO:0051246
Positive regulation of actin
filament polymerization
4
GO:0030838
Regulation of actin cytoskeleton organization
6
GO:0032956
Regulation of cellular component organization
6
GO:0051128
Regulation of gene expression
7
GO:0010468
Notes.
*Process ID in Gene Ontology Database.
In the group represented by patients with schizotypal disorder, 328 proteins were
involved in 59 biological processes (Table 7).
Proteins in the schizotypal disorder group were associated with a large number of
metabolic processes and provided high synthetic activity of the cell. Metabolic processes
coincided for the schizotypal disorder and paranoid schizophrenia groups but were
represented by a wider variety, for example, the presence of purine base synthesis. Also,
many proteins were associated with the catabolic processes of amino acids, organic acids,
Dmitrieva et al. (2022), PeerJ, DOI 10.7717/peerj.13907
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Table 6 Biological processes characterizing significant proteins in the blood serum of patients with
simple schizophrenia (PANTHER).
Metabolic processes
Cellular
processes
Regulation
of
biological
processes
Groups of biological processes
Number of
processes
Process ID*
Macromolecule catabolic process
1
GO:0009057
Movement of cell or subcellular component
1
GO:0006928
Cytoskeleton-dependent
intracellular transport
2
GO:0030705
Cell cycle process
2
GO:0022402
Protein localization to
endoplasmic reticulum
3
GO:0070972
Vesicle-mediated transport
5
GO:0016192
Cellular component organization
8
GO:0016043
Cell–substrate adhesion
1
GO:0031589
Regulation of wound healing
1
GO:0061041
Negative regulation
of catalytic activity
1
GO:0043086
Positive regulation
of metabolic process
1
GO:0009893
Regulation of signal transduction
3
GO:0009966
Regulation of lipase activity
3
GO:0060191
Regulation of transport
4
GO:0051049
Regulation of phospholipase
activity
5
GO:0010517
Regulation of immune response
9
GO:0050776
Notes.
*Process ID in Gene Ontology Database.
and nucleotides. Catabolic processes were also characteristic of proteins from the simple
schizophrenia group. Proteins that characterized cellular processes differed significantly
from the profiles of other patients and were mainly represented by the transport of vesicles
in the synapse, the formation of synaptic endings, and the development of individual brain
structures. In the blood serum of patients with schizotypal disorder, specific chaperone
proteins were also detected that were absent in other groups. The regulatory proteins found
in these patients ensured the functioning of cellular process proteins and regulated the
differentiation of neurons, the activity of glutamate receptors, synaptic signal transmission,
and metabolic processes in the cell.
In the group with acute polymorphic psychotic disorder, 60 proteins were involved in
33 biological processes (Table 8).
The proteins responsible for the biological processes in the acute polymorphic psychotic
disorder group differed significantly from the proteins that characterized the processes
of all other groups. These were mainly proteins associated with the processes of cell
death, including apoptosis of neurons. However, there were also proteins associated
with the process of myelination and the organization of chromosomes. Cell death is
regulated by a large number of proteins, including proteins that increase the activity of
hydrolases and proteases. The processes that inhibit neuronal signal transmission were
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Table 7 Biological processes characterizing significant proteins in the blood serum of patients with
schizotypal disorder (PANTHER).
Metabolic
processes
Cellular
processes
Regulation
of biological
processes
Groups of biological processes
Number of
processes
Process ID*
Cellular macromolecule
metabolic process
1
GO:0044260
Nucleic acid metabolic process
2
GO:0090304
fatty acid metabolic process
2
GO:0006631
Ribonucleotide metabolic process
4
GO:0009259
Organonitrogen compound
metabolic process
4
GO:1901564
Metabolic process
7
GO:0008152
Biosynthetic process
8
GO:0009058
Cellular iron ion homeostasis
1
GO:0006879
Synaptic vesicle cycle
2
GO:0099504
Chaperone-mediated
protein folding
2
GO:0061077
Production of molecular
mediator of immune response
2
GO:0002440
Developmental process
2
GO:0032502
Vesicle-mediated transport
3
GO:0016192
Cellular component organization
3
GO:0016043
Regulation of response
to external stimulus
1
GO:0032101
Regulation of neuron
differentiation
1
GO:0045664
G protein-coupled receptor
signaling pathway
1
GO:0007186
Ionotropic glutamate receptor signaling pathway
1
GO:0035235
Regulation of protein stability
2
GO:0031647
Regulation of response
to stimulus
2
GO:0048583
Regulation of neurotransmitter receptor activity
2
GO:0099601
Regulation of metabolic process
6
GO:0019222
Notes.
*Process ID in Gene Ontology Database.
significantly expressed. Proteins mediating cellular metabolism for these patients did not
show significant differences from the other groups of patients.
DISCUSSION
In the presented work, a comparative proteomic analysis of the blood sera of schizophrenia
spectrum disorders was performed. When comparing the proteomic profiles of patients with
paranoid and simple schizophrenia, acute polymorphic psychotic disorder (APPD), and
schizotypal disorder with the proteomic profile of healthy individuals, highly significant
differences were revealed among all groups. The smallest number of highly significant
differences in protein profiles compared with the control group were found in patients
Dmitrieva et al. (2022), PeerJ, DOI 10.7717/peerj.13907
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Table 8 Biological processes characterizing significant proteins in the blood serum of patients with
acute polymorphic psychotic disorder (PANTHER).
Cellular
processes
Regulation
of biological
processes
Groups of biological processes
Number of
processes
Process ID*
Antigen processing and
presentation
1
GO:0019882
Chromosome organization
1
GO:0051276
Sequestering of calcium ion
1
GO:0051208
Myelination
1
GO:0042552
Transmembrane transport
2
GO:0055085
Cell death
5
GO:0008219
Regulation of cytosolic calcium ion concentration
1
GO:0051480
Negative regulation of T cell
proliferation
1
GO:0042130
Positive regulation of proteolysis
1
GO:0045862
Regulation of B cell proliferation
1
GO:0030888
Regulation of cell cycle process
1
GO:0010564
Negative regulation of signal transduction
1
GO:0009968
Regulation of system process
3
GO:0044057
Regulation of sequestering
of calcium ion
3
GO:0051282
Regulation of programmed
cell death
4
GO:0043067
Regulation of hydrolase activity
6
GO:0051336
Notes.
*Process ID in Gene Ontology Database.
with APPD (p = 0.00635). Usually, such a diagnosis is made for people with a first psychotic
episode, and the outcome can be twofold: either a complete recovery or the development
of schizophrenia. The smallest number of differences in the proteomes of these patients
was from the short duration of the disease and indicated minimal pathological changes in
their organisms (Gehlenborg et al., 2010).
When comparing the proteomic profiles of the blood sera of all the studied groups
of patients, highly significant statistical differences were also obtained. The greatest
number of differences in the protein profiles were revealed between patients with paranoid
schizophrenia and schizotypal disorder. From a clinical point of view, these patients also
differed the most from each other. The smallest number of differences in the proteomic
profiles of patients were found between patients with paranoid schizophrenia and acute
polymorphic psychotic disorder, and (minimal differences) between patients with simple
schizophrenia and schizotypal disorder. Patients with an acute polymorphic psychotic
disorder are very often subsequently diagnosed with paranoid schizophrenia, and the
resulting picture of the comparison of proteomes indicated the common pathogenetic
changes in these disorders. Simple schizophrenia is often similar in its clinical manifestations
to a schizotypal disorder, and changes in the protein spectrum also confirmed the similarity
on the biochemical level (Vora et al., 2018).
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With the help of the international program PANTHER TM GO slim, the main functional
classes of proteins for each studied disorder were determined. Even though most proteins
in all groups were distributed between three main classes: metabolic enzymes, cytoskeleton,
and transmembrane signaling receptors as a result of this comparison, unique results were
obtained for each group of disorders. The data obtained to a certain extent coincided with
those presented in the literature (Woods et al., 2012; Perkovic et al., 2017; Mahadevan et al.,
2017). However, in the studied literature, the detected proteins were not classified according
to their functions and their relationship with pathological mechanisms. According to the
proteins that showed significant differences among all the studied groups, patients with
paranoid schizophrenia were characterized by the main classes of proteins responsible
for translation and transcription processes (about 200 proteins); for the group of simple
schizophrenia—proteins of the receptor apparatus, extracellular matrix, and vesicular
transport (about 100 proteins); for patients with the schizotypal disorder—chaperone
proteins, which are unique to this type of disorder, and metabolic enzymes (75 proteins).
The proteins of patients with an acute polymorphic psychotic disorder were mostly classified
as proteins that metabolize nucleic acids. Proteins of this category were found only in this
group of patients and in the paranoid schizophrenia group. Chromatin-binding/regulating
proteins were also found only in these two groups. This result suggested that for these
groups of patients, the prevalence of proteins of the synthetic cell apparatus reflects active
intracellular processes, which can be justified by the activation of repair processes. It may
indicate a favourable prognosis for the course of the disease (English et al., 2018).
This analysis suggested that in cases of patients with paranoid schizophrenia, repair
processes prevail, which determines the possibility of remission in this group of patients. The
protein classes that predominate in the blood serum of patients with simple schizophrenia
probably indicate a more severe course of the pathological process, reflected on the cellular
level. Schizotypal disorder, characterized by the presence of such classes of proteins as
chaperones, which appear when the body reacts to extreme exposure, speaks primarily to
the highly adaptive abilities of the system with this disorder (Xie et al., 2020). The body’s
response to psychogenic stress, in acute psychosis, is also characterized by a class of proteins
identified in patients with an acute polymorphic psychotic disorder.
For further analysis of the proteins of each group of disorders, specific biological
processes were identified using the program PANTHER again.
As a result of the undertaken research, the processes that characterized each disease were
determined. In patients with paranoid schizophrenia, most of the identified proteins were
involved in the processes of biosynthesis, cell transport, and the location of organelles inside
the cell, that is, in the cell structure formation. A large group of proteins was involved in the
processes of synthesis, functioning, and regulation of the actin cytoskeleton. The identified
proteins were involved in 15 mechanisms of translation and transcription regulation.
A significant number of proteins that characterized the group of patients with simple
schizophrenia regulated the cell’s main metabolic and transport processes. In contrast to
the group with paranoid schizophrenia, in which the processes of anabolism predominated,
the proteins of patients with simple schizophrenia were mainly involved in the processes
of catabolism. The processes of intracellular transport and distribution of organelles, as
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well as the growth and development of neurons, were actively occurring processes in both
simple and paranoid schizophrenia. However, in the group with simple schizophrenia,
most of the transport proteins mediated the transmission of signaling molecules between
cells, receptor transmission, and its regulation. Most proteins in the group of patients
with the schizotypal disorder represented anabolic processes and, thereby, provided the
high synthetic activity of the cell. Some of the metabolic processes coincided with similar
ones in patients with paranoid schizophrenia but were widely represented, such as purine
base synthesis. Proteins that characterized cellular processes in patients with schizotypal
disorder were mainly represented by the transport of vesicles in the synapse, the formation
of synaptic endings, and the processes of neurogenesis. In the blood sera of patients
with schizotypal disorder, specific chaperone proteins were also detected that were not
found in other studied groups. The biological processes presented in the group with acute
polymorphic psychotic disorder differed significantly from the proteins that characterized
the processes of all other groups. Many active processes involved in cell death, including
apoptosis of neurons, were found in patients with APPD, where proteins associated
with the process of myelination and the organization of chromosomes were found. All
these processes cause acute inflammation, which characterizes acute psychosis in cases of
APPD. Thus, the processes specific to each type of studied disorder and characterizing the
pathogenetic and biochemical features of the course of the disease were identified.
CONCLUSIONS
Biological psychiatry has mainly been focused on the study of the relationship between
quantitative changes in individual indicators of a particular disorder. Using the proteomics
method, it was possible to identify the classes of proteins and molecular processes that most
likely characterize some of the most common disorders of the schizophrenic spectrum. This
research provides evidence from the point of view of systems biology for existing significant
differences in biological pathways and molecular mechanisms among schizophrenia
spectrum disorders. According to the proteins that showed significant differences among
all the studied groups, we concluded that the main classes of proteins responsible for
translation and transcription processes are characteristic for patients with paranoid
schizophrenia. These results proved that the processes of repair prevail in these patients,
which leads to the possibility of remission for this group. A significant part of the proteome
of patients with simple schizophrenia referred to proteins that regulate the cell’s main
metabolic and transport processes. However, in contrast to the widely presented metabolic
processes in patients with paranoid schizophrenia, the proteins of patients with simple
schizophrenia mainly regulated the processes of catabolism. The processes of organelle
distribution and intracellular transport were common to both forms of schizophrenia.
For the simple schizophrenia group, most of the transport proteins mediated receptor
transmission and its regulation. These results mainly characterized the greater depth of
the pathological process in this form of schizophrenia. The proteins of patients with
schizotypal disorder mostly coincided with the classes of other groups of patients, except of
chaperone proteins, which were not found in any other disorder. The proteins of patients
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with schizotypal disorder were associated with a large number of metabolic processes
and provided high synthetic activity of the cell. The metabolic processes of patients with
schizotypal disorder and paranoid schizophrenia partially coincided but were represented
by a wide variety. In addition, with this disorder, many proteins were associated with
catabolic processes of amino acids, organic acids, and nucleotides and coincided with
those in patients with the simple form of schizophrenia, which correlated with some
common clinical manifestations of these disorders. These results suggested that, with
further study, chaperone proteins can be a specific marker of the schizotypal disorder. The
proteins of patients with an acute polymorphic psychotic disorder were mostly classified
as proteins that metabolized nucleic acids. Proteins of this category were found only in
these patients and in paranoid schizophrenia. This suggested that for these patients, the
prevalence of proteins of the synthetic cell apparatus could be justified by the activation
of repair processes and may indicate a favourable prognosis of the course of the disease.
Moreover, a large number of active processes involved in cell death, including apoptosis
of neurons, were found in patients with APPD, including proteins associated with the
process of myelination and the organization of chromosomes. All these processes cause
acute inflammation, which characterizes acute psychosis in cases of APPD. These new
results will form the basic knowledge about the molecular mechanisms of the pathogenesis
of these disorders.
However, it will be possible to speak with complete confidence about the discovered
mechanisms and the proteins involved in them after confirming these results in a larger
number of patients and a detailed study of the effect of drug therapy on these processes.
The results obtained may be of interest when studying the pathophysiology and molecular
mechanisms of disorders of the schizophrenic spectrum.
LIMITATIONS
This study has several limitations. First, the group of patients with the studied dis-eases
was small. Serum proteomic studies are very expensive and time-consuming studies. Highquality screening analysis of the proteomic composition of blood serum analyses a huge
number of peptides, identifying thousands of proteins by short ones. The total number of
identified proteins in this study was 4,354. With an increase in the number of patients in the
groups, not only does the cost of work increase significantly, but the volume of processed
data also increases significantly with each sample. Therefore, in this type of proteomic
analysis, we tried to use the minimum possible number of people in the groups. Second,
this study took place in a relatively short period, with consecutive patient recruitment.
The cross-sectional design of this pilot study limited the mechanistic interpretation of
inferred temporal changes, particularly in relation to such factors as age, gender, and
disease duration. Therefore, the sex groups were randomly formed and emphasized the fact
that men are predominantly affected by mental disorders. We conducted additional studies
and investigated whether the obtained data were gender dependent and presented the
results in additional materials. We did not find such a connection. A significant difference
in the ages of patients with APPD and schizotypal disorder with control resulted from
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the early age of manifestation of these disorders. Third, the group of patients with simple
schizophrenia had a significantly longer duration of the disease in comparison with other
groups. However, the fact that negative symptoms and simple schizophrenia predominate
in long term illness is well known (Fenton & McGlashan, 1991). There are various reasons
for this. One of the reasons why psychiatrists cannot determine disease and correctly classify
it by ICD-10 is the severity of symptoms that do not cross the ‘‘threshold’’ border. Finally,
our ability to work and publish results was limited by the size and requirements of the RSF
grant. In this article we published only a part of the results of our work. Using the methods
of statistics and bioinformatics, the manuscript illustrates the processes and pathways that
characterize each disease, which are very important for understanding the peculiarities
of the pathogenesis of mental disorders. We will present full information about altered
proteins in a separate article.
ACKNOWLEDGEMENTS
Mass spectrometric analysis was carried out using the equipment of the ‘‘Human Proteome’’
Core Facility of the Institute of Biomedical Chemistry (IBMC), Moscow.
ADDITIONAL INFORMATION AND DECLARATIONS
Funding
This research was funded by a grant from RSF No 18-15-00053-P (2021-2022). The funders
had no role in study design, data collection and analysis, decision to publish, or preparation
of the manuscript.
Grant Disclosures
The following grant information was disclosed by the authors:
RSF: 18-15-00053-P (2021-2022).
Competing Interests
The authors declare there are no competing interests.
Author Contributions
• Elena Dmitrieva performed the experiments, analyzed the data, prepared figures and/or
tables, authored or reviewed drafts of the article, and approved the final draft.
• Liudmila Smirnova conceived and designed the experiments, performed the experiments,
analyzed the data, authored or reviewed drafts of the article, and approved the final draft.
• Alexander Seregin analyzed the data, prepared figures and/or tables, and approved the
final draft.
• Victor Zgoda performed the experiments, analyzed the data, authored or reviewed drafts
of the article, and approved the final draft.
• Arkadij Semke performed the experiments, authored or reviewed drafts of the article,
and approved the final draft.
• Svetlana Ivanova conceived and designed the experiments, authored or reviewed drafts
of the article, and approved the final draft.
Dmitrieva et al. (2022), PeerJ, DOI 10.7717/peerj.13907
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Human Ethics
The following information was supplied relating to ethical approvals (i.e., approving body
and any reference numbers):
The study was conducted according to the guidelines of the Declaration of Helsinki
and approved by the Ethical Committee of Mental Health Research Institute No 151 from
March 14, 2022 (No 151/1.2022).
Data Availability
The following information was supplied regarding data availability:
Raw data is available at Figshare:
Dmitrieva, Elena (2022): Proteomic profile of serum from patients with schizophrenia
spectrum disorders. figshare. Dataset. https://doi.org/10.6084/m9.figshare.19767709.v1.
Supplemental Information
Supplemental information for this article can be found online at http://dx.doi.org/10.7717/
peerj.13907#supplemental-information.
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