Abstract
Despite the growing importance of the cerebellum as a region highly vulnerable to accumulating molecular errors in schizophrenia, limited information is available regarding altered molecular networks with potential therapeutic targets. To identify altered networks, we conducted one-shot liquid chromatography–tandem mass spectrometry in postmortem cerebellar cortex in schizophrenia and healthy individuals followed by bioinformatic analysis (PXD024937 identifier in ProteomeXchange repository). A total of 108 up-regulated proteins were enriched in stress-related proteins, half of which were also enriched in axonal cytoskeletal organization and vesicle-mediated transport. A total of 142 down-regulated proteins showed an enrichment in proteins involved in mitochondrial disease, most of which were also enriched in energy-related biological functions. Network analysis identified a mixed module of mainly axonal-related pathways for up-regulated proteins with a high number of interactions for stress-related proteins. Energy metabolism and neutrophil degranulation modules were found for down-regulated proteins. Further, two double-hit postnatal stress murine models based on maternal deprivation combined with social isolation or chronic restraint stress were used to investigate the most robust candidates of generated networks. CLASP1 from the axonal module in the model of maternal deprivation was combined with social isolation, while YWHAZ was not altered in either model. METTL7A from the degranulation pathway was reduced in both models and was identified as altered also in previous gene expression studies, while NDUFB9 from the energy network was reduced only in the model of maternal deprivation combined with social isolation. This work provides altered stress- and mitochondrial disease-related proteins involved in energy, immune and axonal networks in the cerebellum in schizophrenia as possible novel targets for therapeutic interventions and suggests that METTL7A is a possible relevant altered stress-related protein in this context.
Highlights
Schizophrenia (SZ) is a complex polygenic psychiatric disorder involving dysregulation of multiples pathways [1] with an estimated prevalence up to 1% in the general population [2] and a high heritability up to 79% [3]
To identify altered proteins related to SZ, we performed a proteomic analysis of human cerebellar lateral cortex protein extracts from 12 male SZ patients and 14 control individuals matched for gender, age and postmortem delay (PMD)
We found that only 56 of the 250 altered proteins had been previously reported in a gene expression study in an induced pluripotent stem cells (iPSC) model of SZ [28], and that only 16 altered proteins had been reported in a microarray assay in human cerebellum [25]
Summary
Schizophrenia (SZ) is a complex polygenic psychiatric disorder involving dysregulation of multiples pathways [1] with an estimated prevalence up to 1% in the general population [2] and a high heritability up to 79% [3]. An environmental double-hit in these phases in a genetically predisposed individual is required for the emergence of the disease [4,5] Based on this hypothesis, cumulative damage in different molecular pathways required for the early development of the central nervous system could contribute to the failure of axonal assembly connections and normal synaptic transmission, which could remain latent until adolescence [6]. A study found that post-weaning social isolation induces altered adult behavior as a result of hyperactivity of the hypothalamic–pituitary–adrenal axis [13] Another animal model used to understand the origin of SZ is the double-hit model in which two hits are required for the emergence of this disorder, the first hit occurring in the prenatal or perinatal phase and a second during adolescence [14,15]. The face and construct validity of these models is demonstrated through several behavioral test analyses that have shown
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