Table 2.
Proteomic studies of schizophrenia and biomarkers discovery using MS-based method in human peripheral fluids. The proteins identified as altered are represented by their entry name as described in UniProt (the corresponding protein name and accession number are described in Supplementary Information, Table S2).
| Author (Year) | Cohort Information | Sample | Type of Sampling | Drug Naive | MS-Based Method | Other Techniques | Quantification Method | Depletion/Enrichment | Altered Proteins | Altered Pathways | Ref. |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Smirnova (2019) | 33 SCZ; 23 BD; 24 CT |
Serum | Individual | Yes | 1DE-LC-MS/MS | ELISA (Q6UB98; P33151) |
MS | Yes/No |
SCZ vs. CTR vs. BD:↑ (A2ML1; ZN189; SMC2; FA12; AACT; APOE; A2GL; IPSP; DMD; CPN2; ABL2; ACTB; ACTG; PRKDC; DCD; RL19; LRP2; LG3BP; ITSN1; ECM1; ARMX4; ANR12; DHX29; DYH5; PINX1; CNDP1; FETUB); ↓ (TNRC18; APOM; CASB; C1QA; RET4; APOD; TETN; CO8G; CO6; DESP; VGFR1; EST1; CADH5; KI67; MYT1; HORN; MAGE1; GULP1) |
SCZ: immune response, cell communication, cell growth and maintenance, protein metabolism, and regulation of nucleic acid metabolism. BD: immune response, regulating transport processes across the cell membrane and cell communication, development of neurons and oligodendrocytes, and cell growth. |
[63] |
| Rodrigues-Amorim (2019) | 45 SCZ (10 FEP; 35 chronic); 43 CT |
Plasma | Individual | No | 1DE-LC-MS/MS | WB (drebrin, GMFB, BDNF, RAB3GAP1, attractin) |
MS | No/Yes | 1302 proteins screened and 34 selected (specific funccctions at CNS level). 5 proteins analyzed. SCZ vs. CT: ↓ (BDNF; GMFB; RB3GAP1) |
Psychoneuroimmune signaling. The available evidence suggests that SCZ causes dysfunction in synaptic, neurotransmission, and neuronal patterns. | [64] |
| Pessoa (2019) | 19 SCZ; 19 BD; 13 CT |
Serum | Pooled | No | LC-MS/MS and LC/ICP-MS | --- | MS | No/No | SCZ vs. CT:↑ (IGHG1; KV320); ↓ (IGKC; IGLC2; TRFE; J3QRN2; IGHG3; KVD28; S4R460; LV325; IGHG2) | Imbalance in the homeostasis of important micronutrients. | [65] |
| Walss-Bass (2019) | 60 SCZ; 20 CT |
Plasma | Pooled | No | 1DE-LC-MS/MS | ELISA (C4A; APOB) | MS | Yes/Yes | Total ID: 10. SCZ vs. CT: ↑ (C4; APOB) |
C4 levels in patients are likely due to the presence of the illness itself, while APOB may be a marker of antipsychotic-induced alterations. | [66] |
| Cooper (2017) | 60 SCZ; 77 CT (Cologne study) |
Serum | Individual | Yes | LC-MS/MS (MRM mode) |
--- | MS | No/No | 77 proteins (68 analyzed after QC) were quantified of a total of 101 selected proteins. SCZ vs. CT: ↑ (HPT; ICI; ANT3; CO4A; AACT; ITIH4; CO9; FCN3; A2AP;APOH); ↓ (APOA2; APOC3; APOA4; APOC1) |
Coagulation, metabolism, and inflammation pathways. Suggest that an increased oxidative stress response may represent an inherent SCZ vulnerability. | [67] |
| Huang (2017) | 20 SCZ; 20 CT |
PBMCs | Individual | No | MALDI-TOF MS | --- | MS | No/No | SCZ vs. CT:↑ (Alpha defensins) | Suggested the activation of immune pathway of PBMCs. | [68] |
| Knochel (2017) | 29 SCZ; 25 BD; 93 CT |
Plasma | Individual | No | LC-MS/MS (MRM mode) | MRI | MS | No/No |
SCZ vs. CT:↑ (APOC1, APOC2, APOC3, APOC4, CFAB, CO3, FCN3, KLKB1, MMP9, PEDF); ↓ (A2AP, ANT3, APOA1, APOA2, APOA4, APOB, APOD, APOE, APOF, APOL1, C1QC, F13B, HEP2, HRG, RET4) SCZ vs. BD: ↑ (APOC2; APOC4; C1QC; CO3; F13B; KLKB1; MMP9); ↓ (A2AP; ANT3; APOA1; APOA2; APOA4; APOB; APOC1; APOC3; APOD; APOE; APOF; APOL1; CFAB; FCN3; HEP2; HRG; PEDF; RET4) |
Altered APOC expression in SCZ and BD was linked to cognitive decline and underlying morphological changes in both disorders. | [69] |
| De Jesus (2017) | 23 SCZ; 14 BD; 4 OD; 12 CT (3 HCF; 9 HCNF) |
Serum | Pooled | No | LC-MS/MS | --- | 2D DIGE | Yes/No | SCZ vs. BD:↑ (C4A; C4B; SAMP) | Altered proteins are associated with an inflammatory response. | [70] |
| Alekseeva (2017) | 10 SCZ; 10 CT |
Serum | Individual | No | 2DE MALDI-TOF/TOF | --- | 2DE | Yes/No | SCZ vs. CT:↑ (APOA4; HPT); ↓ (APOC2; APOC3; SAA1; CLUS; TTHY; ALBU; A1AT; Haptoglobin hp2α (protein ID)) | Altered proteins are associated to lipid homeostasis deregulation, and inflammatory response | [71] |
| Ding (2015) | 44 SCZ; 26 DP; 40 CT |
Serum | Individual | No | SELDI-TOF-MS and MALDI-TOF MS | --- | MS | No/Yes | SCZ:↓ (N-terminal fragment of fibrinogen) | --- | [72] |
| Al Awam (2015) | 26 SCZ; 26 CT |
Serum | Individual | No | MALDI-TOF-MS | GC-MS, FTIR | MS | No/Yes | Total Detected: 94; Significantly different: 11 protein ions. SCZ: ↓ (suggested to be a fragment of APOA1) |
--- | [73] |
| Iavarone (2014) | 32 SCZ; 17 BD; 31 CT |
Saliva | Individual | No | LC-MS/MS | --- | MS | No/No | SCZ vs. CT:↑ (α-defensins 1–4, S100A12, cystatin A and S-derivatives of cystatin B) | SCZ-associated dysregulation of the immune pathway of peripheral white blood cells. Suggested that the dysregulation of the BD group could involve the activation of a more specific cell type than that of the SCZ group. | [74] |
| Li (2012) |
10 SCZ; 10 CT |
Serum | Individual | Yes | LC-MS/MS | ELISA | MS | Yes/No | Total ID: 1344. SCZ vs. CT: ↑ (CO8B; CD5L; DOPO; IGHG4; IGHM; KNG1; PI16; PGRP2; ITIH4; PLTP; IPSP; IGK@ protein; IGL@ protein); ↓ (AMPN; APOC2; APOF; C4BPB; APOL1; FA7; GGH; ICAM2; ALS; isoforms 2 of ITIH4; LBP; PROS; ZNF57) |
Dysregulation of the alternative complement pathway in SCZ patients. | [75] |
| Jaros (2012) | 20 SCZ; 20 CT |
Serum | Individual | Yes | LC-MS/MS | ELISA (RET4; FCN3) |
MS | Yes/Yes ⁑ | Total ID: 312. Significantly different: 35. Phospho altered: 72. SCZ vs. CT: ↑ (K2C6B; FCN3; SRBS1; NUCB1; K1C9; NUDT6; ALS2; IBP3; MAST1; CFAB; C4BPA; FHR3; ITIH3; CO6; AGRE1); ↓ (CAH1; RET4; LRRC7; FR1L6; KI21B; TETN; KIF27; APOA1; APOA2; MYOF; FIBA; CCD57; SMC1A; K1C14; PHLD; LIFR; XIRP1 ↓; WDR19; SMC4; SAGE1) |
Acute phase; Complement and coagulation system; Immune Response. | [76] |
| Raiszadeh (2012) | 23 SCZ; 55 CT For analysis: 4 SCZ; 4 CT (2nd pool) |
Sweat | Pooled | No | LC-MS/MS and LC-MS/MS-MRM | --- | MS | No/No | 1st set Total ID: 150; 2nd set Total ID: 185; MRM: 30. SCZ vs. CT: ↑ (ZA2G; ANXA5; ARG2; BLMH; CALL5; CASPE; CDSN; CSTA; DCD; Desmoglein; DJ-;G3PDH; KLK11; KRT10; PRDX1; PEBP1; S100A7; THIO); ↓ (PIP) |
Metabolic process. | [77] |
| Herberth (2011) | 19 SCZ; 19 CT |
PBMCs | Individual | Drug naïve/ treated | LC-MS/MS | WB (ALDOC, GAPDH, LDHB, PGK1, TPIS) |
MS | No/Yes |
Unstimulated PBMCs:↑ (CNDP2; Uncharacterized protein KIAA0423; LDHB); ↓ (COTL1; GPI; HSP72). Stimulated PBMCs: ↑ (ALDOC; GAPDH; HNRPK; LDHB; MYH14; MYH15; NAMPT; PGK1; PPIA; TPIS; PKLR; PGAMA4); ↓ (CH60). |
Glycolytic pathway, Immune response. | [78] |
| Levin (2010) | 22 SCZ; 33 CT |
Serum | Individual | No | LC-MS/MS | ELISA (APOA1; APOA2; APOA4; FETUA) |
MS | Yes/No | Total ID: 1411. Significantly different: 10. SCZ vs. CT: ↑ (CD5L; IGHM; F13B; TRFE; APOD; APOA1; FETUA; APOA4; APOA2; APOC1) |
Lipid metabolism; molecular transport; Immune response. |
[79] |
| Craddock (2008) | 15 SCZ; 15 CT |
PBMCs | Individual | Yes | SELDI-TOF-MS | ELISA (α-defensins) |
MS | No/Yes | SCZ:↑ (α-defensins) | Immune alteration. | [80] |
| Wan (2007) |
42 SCZ; 46 CT |
Plasma | Individual | No | MALDI-TOF MS | --- | 2-DE | No/No | SCZ vs. CT:↑ (Haptoglobin a; a1-Antitrypsin; a1-Microglobulin; SAMP; ANT3; VTDB); | Evidence indicates that chronic systemic inflammation may be an aetiological agent of the pathophysiology of SCZ. |
[81] |
BD: bipolar disorder; CNS: central nervous system; CT: controls; DP: depression; ELISA: enzyme-linked immunosorbent assay; FEP: first-episode psychosis; HCF: familiar healthy control; HCNF: non-familiar healthy control; OD: other disorders; SCZ: schizophrenia; WB: Western blot; ⁑ Despite the enrichment method used, the flow-through was also analyzed.