Label-free quantitative proteomic analysis reveals dysfunction of complement pathway in peripheral blood of schizophrenia patients: evidence for the immune hypothesis of schizophrenia

Abstract

Schizophrenia is a complex mental disease caused by a combination of serial alterations in genetic and environmental factors. Although the brain is usually considered as the most relevant organ in schizophrenia, accumulated evidence suggests that peripheral tissues also contribute to this disease. In particular, abnormalities of the immune system have been identified in the peripheral blood of schizophrenia patients. To screen the serum proteomic signature of schizophrenia patients, we conducted shotgun proteomic analysis on serum samples of schizophrenia patients and healthy controls. High-abundance proteins were eliminated by immunoaffinity before LC-MS/MS analysis. The multivariate statistical test partial least squares-discriminant analysis (PLS-DA) was applied to build models for screening out variable importance in the projection (VIP) and 27 proteins were identified as being responsible for discriminating between the proteomic profiles of schizophrenia patients and healthy controls. Pathway analysis based on these 27 proteins revealed that complement and coagulation cascades was the most significant pathway. ELISA-based activity analyses indicated that the alternative complement pathway was suppressed in schizophrenia patients. Ingenuity pathways analysis was used to conduct the interaction network of 27 proteins. The network exhibited common features such as, nervous system development and function, humoral immune response and inflammatory response, and highlighted some proteins with important roles in the immune system, such as hub nodes. Our findings indicate dysregulation of the alternative complement pathway in schizophrenia patients. The protein interaction network enhances the interpretation of proteomic data and provides evidence that the immune system may contribute to schizophrenia.

Biomarkers in schizophrenia: A focus on blood based diagnostics and theranostics

“…DAAM2, one of five differentially expressed genes, returned to control levels in the whole blood when people were in remission after their first psychotic episode, suggesting this mRNA could be altered by antipsychotics and may be a potential marker for treatment response. Taken together, there is only downregulation of intercellular adhesion molecule in people with Sz that were replicated in at least two microarray studies [138,140] . Other studies have identified markers that may be of use in identifying people who are at risk of developing the disorder, such as the up-regulation of DEFA in T cells and plasma from people with Sz, and both their affected or unaffected monozygotic twin [136] .…”

“…It is possible that some of the differential patterns reported to exist in people with Sz can be used for diagnostic purposes. However, only a few studies reported the sensitivity and specificity of the discri minability of their markers [108,123,125,130,138,140,141] , leaving doubt as to the potential of the other molecules to act as markers. To try and assess the utility of these disparate markers, performing a metaanalysis based on the categories we used here might be helpful to identify potential markers that have large and consistent effect size across studies.…”

“…In addition, 27 serum proteins were identified as discriminating between people with Sz and healthy controls [138] and highlighted some proteins among them with important roles in the immune system. It has been reported that dysregulation of 4 serum analytes [uprefulation of 2piperidinec carboxylic acid, along with the downregulation of 6deoxymannofuranose, galactoseoxime, and a serum peptide (m/z 3177)] have the best discriminating value between people with Sz, and controls [141] , indicating that metabolomics and proteomic approaches can be used in the biomarker research.…”

“…In psychiatry, such studies have involved the use of whole blood [129131] , lymphocytes [132] or PBMC samples [133135] to identify potential biomarkers for Sz. Other studies examined proteomics information in RBC [109] , T cells [136] , and serum [61,109,137,138] in attempts to answer the same question. This approach has typically led to a large set of mRNAs or proteins being proposed as possible biomarkers in Sz but most findings await replication.…”

Circulating biomarkers in schizophrenia: a proteomics perspective

“…On Table 2 are presented the studies published on blood serum and plasma, spanning from 2006; after this search 7 studies on serum of patients with SCZ and 6 on plasma were found. The preferred quantitative method of analysis of the serum samples was label-free MS, using LC-MS E [62][63][64] or MS1 signal intensity [65][66][67]. On the other hand, from the 6 studies in plasma, 5 used 2-DE-MS analysis [50,[69][70][71][72] and one study using targeted mass spectrometry MRM technique to quantify 42 plasma proteins [73].…”