EV-ASSOCIATED MICRORNAS AS POTENTIAL BIOMARKERS FOR 22Q11.2DS AND ASSOCIATED DISORDERS IN AN IPSC MODEL; COMPARISON OF CENTRAL AND PERIPHERAL BIOMARKERS

This research aimed to connect the cell intrinsic and extrinsic miRNA profiles from 22q11.2DS patient induced pluripotent stem cell (iPSC) derived neurons and compare this to existing blood extracellular vesicle (EV) profiles from 22q11.2DS patients. This could provide the basis for biomarker discovery in 22q11.2DS, and potentially idiopathic schizophrenia, that can capture neuronal microRNA (miRNA) dysregulation. miRNAs are key post-transcriptional regulators that fine-tune gene expression and are essential for normal brain development and function. Dysregulation of these molecules has been implicated in several psychiatric conditions, including schizophrenia. The current work is motivated by the markedly elevated risk, approximately 25-fold, for developing schizophrenia among individuals with 22q11.2DS. The deletion removes a critical region of chromosome 22, including DGCR8, a core component of the microprocessor complex and master regulator of miRNA biogenesis, providing a mechanistic link between the genetic lesion and widespread miRNA disruption.
We extracted miRNAs from both neurons and EVs, isolated from conditioned media, and performed qRT-PCR for analysis, allowing us to establish whether vesicle-packaged miRNAs reflect the intracellular miRNA abnormalities seen in the disorder. We have successfully monitored miRNAs in EVs isolated from the conditioned media and have preliminary evidence of correspondence between candidate miRNAs in the EVs and those extracted from the neurons. Our approach has the potential to validate peripheral miRNA biomarkers in terms of changes in the CNS in a 22q11.2DS model that may also have relevance for idiopathic schizophrenia.