Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains

Abstract

Schizophrenia is an incurable and debilitating mental disorder that may affect up to 1% of the world population. Morphological, electrophysiological, and neurophysiological studies suggest that the corpus callosum (CC), which is the largest portion of white matter in the human brain and responsible for inter-hemispheric communication, is altered in schizophrenia patients. Here, we employed mass spectrometry-based proteomics to investigate the molecular underpinnings of schizophrenia. Brain tissue samples were collected postmortem from nine schizophrenia patients and seven controls at the University of Heidelberg, Germany. Because the CC has a signaling role, we collected cytoplasmic (soluble) proteins and submitted them to nano-liquid chromatography-mass spectrometry (nano LC-MS/MS). Proteomes were quantified by label-free spectral counting. We identified 5678 unique peptides that corresponded to 1636 proteins belonging to 1512 protein families. Of those proteins, 65 differed significantly in expression: 28 were upregulated and 37 downregulated. Our data increased significantly the knowledge derived from an earlier proteomic study of the CC. Among the differentially expressed proteins are those associated with cell growth and maintenance, such as neurofilaments and tubulins; cell communication and signaling, such as 14-3-3 proteins; and oligodendrocyte function, such as myelin basic protein and myelin-oligodendrocyte glycoprotein. Additionally, 30 of the differentially expressed proteins were found previously in other proteomic studies in postmortem brains; this overlap in findings validates the present study and indicates that these proteins may be markers consistently associated with schizophrenia. Our findings increase the understanding of schizophrenia pathophysiology and may serve as a foundation for further treatment strategies.

Increased density of DISC1-immunoreactive oligodendroglial cells in fronto-parietal white matter of patients with paranoid schizophrenia

“…A majority of the encoded proteins were involved in myelin metabolism, thus confirming previous observations made by others [51,52]. Not surprisingly, many OL genes are downregulated in schizophrenia (reviewed in [53][54][55][56] and others), but a number of upregulated genes have also been identified [56]. Among upregulated OL/myelin genes are myelin-associated oligodendrocyte basic protein [54], cyclin D1, and phosphorylated retinoblastoma protein [57]).…”

The Nuclear Proteome of White and Gray Matter from Schizophrenia Postmortem Brains

“…Moreover, studies of silencing and super-expression of proteins showed a crucial role of hnRNP proteins in the myelination of neurons by oligodendrocytes, independently of the indirect regulation of quaking proteins as previously proposed [45,46]. This dysfunction in myelination was related to dysregulation of the synaptic connection [47,48,49]. One of these proteins was HNRNPC, which was found at decreased levels in SCZ patients compared to controls in this study.…”

Circulating biomarkers in schizophrenia: a proteomics perspective

“…Initially, the great majority of the studies were performed in post-mortem brain tissue and it is easy to find large screenings in several brain areas, such as frontal [35] and prefrontal cortex [36]; the corpus callosum [37]; the temporal lobe [38] or the hippocampus [39] (citations as examples, for an extensive review refer to [14]). Later on, other tissues [40,41] or cell populations [42] and body fluids (Tables 1 and 2) or even animal models (e.g.…”