Abstract
Because of the role played by miRNAs in post-transcriptional regulation of an array of genes, their impact in neuropsychiatric disease pathophysiology has increasingly been evident. In the present study, we assessed microRNA expression in prefrontal cortex (Brodmann area 10) of a well-characterized cohort of major depressed, bipolar, and schizophrenia subjects (obtained from Stanley Neuropathology Consortium; n = 15 in each group), using high throughput RT-PCR plates. Discrete miRNA alterations were observed in all disorders, as well as in suicide subjects (pooled across diagnostic categories) compared to all non-suicide subjects. The changes in the schizophrenia group were partially similar to those in the bipolar group, but distinct from changes in depression and suicide. Intriguingly, those miRNAs which were down-regulated in the schizophrenia group tended to be synaptically enriched, whereas up-regulated miRNAs tended not to be. To follow this up, we purified synaptosomes from pooled samples of the schizophrenia vs. control groups and subjected them to Illumina deep sequencing. There was a significant loss of small RNA expression in schizophrenia synaptosomes only for certain sequence lengths within the miRNA range. Moreover, 73 miRNAs were significantly down-regulated whereas only one was up-regulated. Strikingly, across all expressed miRNAs in synaptosomes, there was a significant inverse correlation between the fold-change of a given miRNA seen in schizophrenia and its synaptic enrichment ratio observed in controls. Thus, synaptic miRNAs tended to be down-regulated in schizophrenia, and the more highly synaptically enriched miRNAs tended to show greater down-regulation. These findings point to some deficit in miRNA biogenesis, transport, processing or turnover in schizophrenia that is selective for the synaptic compartment. A novel class of ncRNA-derived small RNAs, shown to be strongly induced during an early phase of learning in mouse, is also expressed in man, and at least one representative (SNORD85) was strongly down-regulated in schizophrenia synaptosomes.
Highlights
Profiling gene expression within human brain tissue is a basic starting point for understanding neuropsychiatric diseases
Five considerations provide compelling evidence that there was no overall loss of miRNA expression in the schizophrenia samples: a) Overall miRNA abundance was unchanged between controls and schizophrenia groups in Experiment 1, using both normalized and non-normalized data. b) Of the miRNAs that were significantly changed in schizophrenia, twice as many were up-regulated as down-regulated. c) We used median normalization of Ct values which removes any individual changes in overall miRNA abundance due to random degradation. d) Two samples which did show overt overall loss of miRNA abundance were excluded from analysis. e) we calculated RNA quality values for the control and schizophrenia samples that were assayed by TLDA, using leftover RNA
Synaptosomes were prepared from schizophrenia vs. controls (5 pools of 3 individuals in control group and 6 pools of 2– 3 individuals in schizophrenia group) and subjected to Illumina deep sequencing in the range from 15–40 nt
Summary
Profiling gene expression within human brain tissue is a basic starting point for understanding neuropsychiatric diseases This information is critical for identifying specific genes and coordinated sets of genes that are altered in disease – these include genes which show altered expression due to genetic causes (e.g., SNPs or CNVs), but those which reflect altered pathways that contribute to pathogenesis (e.g. synaptic signaling, transcription factors, or epigenetic regulation). MicroRNAs are regulators of gene expression and protein translation in many tissues, including brain; it is imperative to catalog the expression of miRNAs and other small RNAs in key regions of human brain as well as in major neuropsychiatric diseases This may lead to new biomarkers for diagnostic subtyping and treatment response, as well as new therapeutic targets and new clues regarding etiology
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