Development of Novel Transdiagnostic Neural-Derived Exosomal miRNA-based Biomarkers for Suicidality

Suicide is among the top 10 causes of death for individuals of all ages in the developed world, and it is the second leading cause in persons aged 10 to 34 years. Despite the high prevalence, the underlying etiopathogenesis of suicide remains poorly understood. In addition, a lack of suitable biological markers leads to subjective, syndromal diagnosis and a poor treatment outcome for a substantial proportion of suicidal patients. Thus, not only is there a need to identify novel molecular pathways but also biological markers that can identify and/or stratify the risk of suicidality in patients. These markers would ideally be transdiagnostic, which would enable clinicians to identify meaningful biological risk factors for suicide across a range of mental health conditions. MicroRNAs (miRNAs), a subclass of non-coding RNAs that regulate gene expression via post-transcriptional mechanisms, are generating enormous interest as regulators of disease pathologies and in developing targeted novel therapeutic drugs. Cells release miRNAs into the peripheral circulation in exosomes that bear cell-type specific surface markers. Using specific markers, we have isolated neural-derived exosomes (NDE) from blood plasma and found that these exosomes are enriched with miRNAs that are expressed in the brain. Our novel approach provides an avenue to detect NDE miRNAs in blood, which can potentially be used as predictive biomarkers for psychiatric illnesses and/or tracking treatment outcomes. In a pilot study, we found that the expression of specific sets of plasma NDE miRNAs was associated with suicidality among MDD patients. What is not known is whether miRNAs associated with suicidal behavior are unique to MDD patients, if they are also associated with suicidality in people with other mental disorders, or if each disorder has a unique set of miRNAs associated with suicidality. Our overarching hypothesis is that a subset(s) of neural-derived exosomal miRNAs and their variants will show differential expression that will target mRNAs and generate biological pathways specific to suicidality transdiagnostically. To test this, we will examine the genome-wide expression of miRNAs in plasma NDE in the following groups of subjects (n=40/group): 1) MDD, 2) bipolar disorder, 3) schizophrenia, and 4) healthy controls. Participants will be patients with and without recent suicide attempts (SA) (within two weeks). With this, the study plans to determine if: 1) suicidality is associated with differences in the expression of NDE miRNAs transdiagnostically; 2) specific miRNA/mRNA regulatory pathway(s) contribute to suicide pathogenesis transdiagnostically; and 3) changes in suicide-associated miRNAs are explained by modifications in their promoter DNA methylation. This first-of-its-kind study will provide a novel avenue to identify miRNAs as “molecular tools’’ for developing a biomarker for suicidality. It will also provide much-needed pilot data for an NIMH submission of a more extensive study.