Sodhi Lab receives IGNITE award to launch UIC Brain Collection for Psychiatric Disorders
There is strong evidence that psychiatric disorders run in families, and therefore it is important to study the genetic mechanisms which are abnormal in the brains of these patients. To achieve this, investigations in human postmortem brain are essential. Therefore Monsheel Sodhi together with a group of scientists from the Departments of Psychiatry, Pathology and Kinesiology, has launched a collection of postmortem brain tissue from psychiatric patients and subjects from the general population. The UIC Brain Collection will help scientists to answer critical questions about the biology underpinning suicide and psychiatric disorders, by comparing different regions of the brains of psychiatric patients with those of non-psychiatric individuals. These studies have the potential to identify new targets for the development of improved treatments and also, to identify biochemical markers that could be used to predict suicide risk. This project addresses an unmet clinical need and could help to prevent the suffering of psychiatric patients and their families.
RNA editing of the glutamate and serotonin system is abnormally regulated in major psychiatric disorders.
RNA editing is a post-transcriptional process which is predicted to modify up to 2000 transcripts in addition to 16% of known microRNAs1. Of particular interest in psychiatry research, several glutamate receptors, a GABA receptor and a 5-HT receptor are impacted by RNA editing. This RNA editing process occurs after hydrolytic deamination of 1-5 adenosine (A) residues, by enzymes called the Adenosine Deaminases Acting on RNA enzymes (or 'ADARs').
The double-stranded RNA loop of the human 5-HT2C receptor transcript. ADAR enzymes have been shown to bind only to double-stranded RNA. The specific sites of activity of ADARs 1 and 2 are indicated.
RNA editing of the 5-HT2C receptor produces structural changes that alter G-protein coupling and constitutive activity of the receptor in vitro. The fully-edited isoform of the 5-HT2RC (VGV) has >40-fold decrease in serotonergic potency2. Mutant mice solely expressing the fully edited (VGV) isoform of the receptor (5-HT2CRVGV) exhibited >20-fold increases in 5-HT2CR protein levels in multiple brain regions. These mice modeled some of the symptoms of Prader-Willi syndrome3. Furthermore, mouse models of learned helplessness4 and anxiety5 also have altered 5-HT2C RNA editing.
We have analyzed the expression of RNA editing enzymes in the dorsolateral prefrontal and anterior cingulate cortices of postmortem subjects diagnosed with schizophrenia, major depression (MDD), bipolar disorder, and a comparison group (total n=60-115). We have detected altered expression of specific mRNAs that encode ADAR enzymes in major depressive suicide victims compared with patients who did not commit suicide. We have also identified increased levels of 5-HT2C and GluA2 RNA editing in suicides. Therefore RNA editing may play a role in the pathophysiology of suicide13. These data indicate that RNA editing biomarkers may be used to identify patients with psychiatric disorders who die by suicide. Small molecule inhibitors of RNA editing may also represent novel targets for psychotropic drug development.
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