Deletions on chromosome 22q11.2 are a strong genetic risk factor for development 
of schizophrenia and cognitive dysfunction. We employed shotgun liquid 
chromatography-mass spectrometry (LC-MS) proteomic and metabonomic profiling 
approaches on prefrontal cortex (PFC) and hippocampal (HPC) tissue from 
Df(16)A+/- mice, a model of the 22q11.2 deletion syndrome. Proteomic results 
were compared with previous transcriptomic profiling studies of the same brain 
regions. The aim was to investigate how the combined effect of the 22q11.2 
deletion and the corresponding miRNA dysregulation affects the cell biology at 
the systems level. The proteomic brain profiling analysis revealed PFC and HPC 
changes in various molecular pathways associated with chromatin remodelling and 
RNA transcription, indicative of an epigenetic component of the 22q11.2DS. 
Further, alterations in glycolysis/gluconeogenesis, mitochondrial function and 
lipid biosynthesis were identified. Metabonomic profiling substantiated the 
proteomic findings by identifying changes in 22q11.2 deletion syndrome 
(22q11.2DS)-related pathways, such as changes in ceramide phosphoethanolamines, 
sphingomyelin, carnitines, tyrosine derivates and panthothenic acid. The 
proteomic findings were confirmed using selected reaction monitoring mass 
spectrometry, validating decreased levels of several proteins encoded on 
22q11.2, increased levels of the computationally predicted putative miR-185 
targets UDP-N-acetylglucosamine-peptide N-acetylglucosaminyltransferase 110 kDa 
subunit (OGT1) and kinesin heavy chain isoform 5A and alterations in the 
non-miR-185 targets serine/threonine-protein phosphatase 2B catalytic subunit 
gamma isoform, neurofilament light chain and vesicular glutamate transporter 1. 
Furthermore, alterations in the proteins associated with mammalian target of 
rapamycin signalling were detected in the PFC and with glutamatergic signalling 
in the hippocampus. Based on the proteomic and metabonomic findings, we were 
able to develop a schematic model summarizing the most prominent molecular 
network findings in the Df(16)A+/- mouse. Interestingly, the implicated pathways 
can be linked to one of the most consistent and strongest proteomic candidates, 
(OGT1), which is a predicted miR-185 target. Our results provide novel insights 
into system-biological mechanisms associated with the 22q11DS, which may be 
linked to cognitive dysfunction and an increased risk to develop schizophrenia. 
Further investigation of these pathways could help to identify novel drug 
targets for the treatment of schizophrenia.