Schwarcz, R. | Search bioRxiv

bioRxiv2026

The single nucleotide polymorphism rs1053230 modulates kynurenine 3-monooxygenase stability and is associated with cognitive and mood phenotypes

BackgroundThe single nucleotide polymorphism (SNP) rs1053230 within the kynurenine 3-monooxygenase (KMO) gene encodes either an arginine (CGC) or cysteine (TGC) at amino acid residue 452. The rs1053230 genotype is associated with alterations in KMO expression and activity, and impaired cognition. Additionally, KMO intronic SNP rs2275163 is associated with schizophrenia endophenotypes. However, the direct functional consequences of these SNPs on KMO function have never been investigated. MethodsHere we performed the first in vitro cell-based examination of the rs1053230 genotype on KMO expression, activity, cellular localisation and KMO-protein interactions, as well as examination of the effects of rs1053230 on schizophrenia-relevant clinical measures. We also examined the effects of rs2275163 genotype on KMO pre-mRNA stability and alternative splicing. ResultsHEK293T cells expressing KMO-Arg452 or KMO-Cys452 with a red fluorescent protein (RFP) tag produced equivalent levels of KMO mRNA, protein and enzymatic activity, and localised to mitochondria to the same extent. However, cycloheximide-mediated inhibition of protein translation revealed a striking reduction in protein stability of KMO-Arg452-RFP. KMO-RFP-trap pull-down followed by tandem liquid-chromatography-mass spectrometry (LC-MS/MS) identified dramatic differences in protein partners between KMO variants. Indeed, gene ontology-term enrichment analysis revealed that terms associated with synaptic function were more highly enriched amongst KMO-Cys452 interacting proteins. rs1053230 genotype was found to associate with chronic, trait-like depressive mood symptoms in patients. rs2275163 genotype had no effect on KMO pre-mRNA. ConclusionsDifferences in protein stability and protein-protein interactions may underlie the mechanisms by which the KMO rs1053230 genotype influences neuronal function, leading to cognitive differences in psychiatric conditions.

molecular biology↗

bioRxiv2026

Identification of a miRNA signature for schizophrenia in plasma-derived extracellular vesicles

Background and Hypothesis: Extracellular vesicles (EVs) are phospholipid bilayer vesicles released from cells containing proteins, lipids and nucleic acids derived from the parent cell. Alterations in miRNA expression within blood-derived EVs have been proposed as potential biomarkers of disease. Specifically, identification of differentially expressed miRNAs in patients with schizophrenia (SZ) compared to healthy individuals could be used as a "miRNA signature" to aid in diagnosis and treatment. We therefore aimed to identify differentially expressed miRNAs in plasma-derived EVs between people living with SZ and healthy controls and to correlate miRNA levels with SZ-relevant clinical measures. Study Design: Plasma-derived EVs were isolated from a cohort of 33 individuals with SZ and 34 controls. Expression of 84 miRNAs was examined using a RT-qPCR panel. Study Results: Three miRNAs (hsa-miR-30e-5p, hsa-miR-103a-3p, hsa-miR-200b-3p) were differentially expressed between controls and patients. Gene ontology analysis of putative target genes shared between these miRNAs revealed enrichment of biological process terms related to neurogenesis. Analysis of miRNA expression compared to clinical measures showed that hsa-miR-103a-3p expression was associated with working memory and negatively correlated with white matter integrity in the combined patient-control group. Conclusions: We have identified a miRNA signature for SZ in plasma-derived EVs and shown for the first time that hsa-miR-30e-5p expression is significantly increased in plasma-derived EVs in SZ. The genetic links between differentially expressed miRNAs and neurogenesis, along with the correlations of hsa-miR-103a-3p with working memory and white matter integrity may underlie the functional importance of altered expression of the identified miRNAs in SZ.

genetics↗