Proteomics Research in Schizophrenia

Abstract

Despite intense scientific efforts, the neuropathology and pathophysiology of schizophrenia are poorly understood. Proteomic studies, by testing large numbers of proteins for associations with disease, may contribute to the understanding of the molecular mechanisms of schizophrenia. They may also indicate the types and locations of cells most likely to harbor pathological alterations. Investigations using proteomic approaches have already provided much information on quantitative and qualitative protein patterns in postmortem brain tissue, peripheral tissues and body fluids. Different proteomic technologies such as 2-D PAGE, 2-D DIGE, SELDI-TOF, shotgun proteomics with label-based (ICAT), and label-free (MSE) quantification have been applied to the study of schizophrenia for the past 15 years. This review summarizes the results, mostly from brain but also from other tissues and bodily fluids, of proteomics studies in schizophrenia. Emphasis is given to proteomics platforms, varying sources of material, proposed candidate biomarkers emerging from comparative proteomics studies, and the specificity of the putative markers in terms of other mental illnesses. We also compare proteins altered in schizophrenia with reports of protein or mRNA sequences that are relatively enriched in specific cell types. While proteomic studies of schizophrenia find abnormalities in the expression of many proteins that are not cell type-specific, there appears to be a disproportionate representation of proteins whose synthesis and localization are highly enriched in one or more brain cell type compared with other types of brain cells. Two of the three proteins most commonly altered in schizophrenia are aldolase C and glial fibrillary acidic protein, astrocytic proteins with entirely different functions, but the studies are approximately evenly divided with regard to the direction of the differences and the concordance or discordance between the two proteins. Alterations of common myelin-associated proteins were also frequently observed, and in four studies that identified alterations in at least two, all differences were downwards in schizophrenia, consistent with earlier studies examining RNA or targeting myelin-associated proteins.

The neurobiology of transition to psychosis

“…[58][59][60][61][62][63][64] Arguably, of all the expressed brain proteins with recorded abnormalities, astrocytic and oligodendrocytic proteins appear to be the most consistently affected in patients with schizophrenia. 65 Second, recent genomic studies indicate a cardinal role for oligodendrocyte-related genetic polymorphisms in patients with schizophrenia. [66][67][68] Neuregulin-1, a well-established candidate marker for schizophrenia, results in a schizophrenia-like phenotype (increased dopamine transmission and reduced social interaction), possibly through oligodendrocyte dysfunction and defective myelination.…”

Circulating biomarkers in schizophrenia: a proteomics perspective

“…In the genetics field studies have been performed using: genome wide association studies (GWAS), next-generation sequencing, copy-number variations (CNV) and microarrays, with different study designs using the general population, twins and family studies [14,15] linking SCZ with rare genetic variations, stating that SCZ has a strong genetic component. The heritability is estimated to be close to 80%, although the heterogeneous manifestations of the disease and its complex genetic architecture indicate a non-mendelian complex mode of transmission [15,16].…”

“…Overall, it is possible to state that a need for biomarkers of psychiatric diseases at different levels (diagnosis, prognosis, treatment resistance…) is pressing and that to achieve this not only gene expression and DNA variations should be studied and determined, but also the abundance and modifications of the proteins and their distribution at the subcellular level [14]. In particular, efforts to find protein altered patterns in circulating fluids have increased interest given that such fluids are relatively easier to access than the brain in order to perform clinical testing but, firstly, to enable relevant research.…”

“…Proteomics aims to describe and understand biological processes based on the qualitative or quantitative comparison of proteomes [14], especially in diseased versus control cases. The great development of this area may be attributed to the technological advances in mass spectrometry (MS), optimization in sample preparation and computer sciences that are now able to deal with the large amount of information that is nowadays generated by the MS-based technologies [25,26].…”

The impact of advanced proteomics in the search for markers and therapeutic targets of bladder cancer

“…For instance, numerous transcripts give rise to more than one protein through alternative splicing or alternative PTMs, including phosphorylation, glycosylation, and acetylation, that profoundly affect protein activity and lead to multiple protein products from the same gene. 13 From microarray data, Shimwell et al 14 detected that the expression of HAI-1 and midkine mRNA was elevated in Ta BC but did not increase further with increasing stages. This suggests that the urinary protein levels and mRNA expression do not correlate across disease stages.…”