Biology subjects

Olla, I.

Publications and source records attributed to Olla, I..

3 recordsLinked to original sources

bioRxiv2022

Pathogenic mis-splicing of CPEB4 in schizophrenia

Schizophrenia (SCZ) is caused by a complex interplay of polygenic risk and environmental factors, which might alter regulators of gene expression leading to pathogenic mis-expression of SCZ risk genes. The RNA binding protein family CPEB (CPEB1, CPEB2, CPEB3, CPEB4) regulates the translation of target RNAs bearing CPE sequences in their 3UTR (approximately 40% of overall genes). We previously identified CPEB4 as a key dysregulated translational regulator in autism spectrum disorder (ASD), proving that its neuronal-specific microexon (exon 4) is mis-spliced in brains of ASD probands, leading to concerted underexpression of a plethora of high confidence ASD-risk genes. The genetic and pathogenic mechanisms shared between SCZ and ASD make it plausible that mis-splicing of CPEB4 might occur also in SCZ patients, leading to downstream altered brain expression of multiple SCZ-related genes. In this study, we first analyzed Psychiatric Genomics Consortium GWAS data and found significant enrichment of SCZ-associated genes for CPEB4-binder transcripts. We also found decreased inclusion of CPEB4 microexon in postmortem prefrontal cortex of SCZ probands. This mis-splicing is associated with decreased protein levels of SCZ-associated genes that are targets of CPEB4. Interestingly, this happens specifically in individuals with low exposure to antipsychotic medication. Finally, we show that mild overexpression of a CPEB4 transcript lacking exon 4 (CPEB4{Delta}4) in mice suffices to induce decreased protein levels of SCZ genes targeted by CPEB4; these mice are also characterized by SCZ-linked behaviors. In summary, this study identifies aberrant CPEB4 splicing and downstream mis-expression of SCZ-risk genes as a novel etiological mechanism in SCZ.

neuroscience↗

bioRxiv2020

High concordance between hippocampal transcriptome of the intraamygdala kainic acid model and human temporal lobe epilepsy

ObjectivePharmacoresistance and the lack of disease-modifying actions of current anti-seizure drugs persist as major challenges in the treatment of epilepsy. Experimental models of chemoconvulsant-induced status epilepticus remain the models of choice to discover potential anti-epileptogenic drugs but doubts remain as to the extent to which they model human pathophysiology. The aim of the present study was to compare the molecular landscape of the intraamygdala kainic acid model of status epilepticus in mice with findings in resected brain tissue from patients with drug-resistant temporal lobe epilepsy (TLE). MethodsStatus epilepticus was induced via intraamygdala microinjection of kainic acid in C57BL/6 mice and gene expression analysed via microarrays in hippocampal tissue at acute and chronic time-points. Results were compared to reference datasets in the intraperitoneal pilocarpine and intrahippocampal kainic acid model and to human resected brain tissue (hippocampus and cortex) from patients with drug-resistant TLE. ResultsIntraamygdala kainic acid injection in mice triggered extensive dysregulation of gene expression which was [~]3-fold greater shortly after status epilepticus (2729 genes) when compared to epilepsy (412). Comparison to samples of patients with TLE revealed a particular high correlation of gene dysregulation during established epilepsy. Pathway analysis found suppression of calcium signalling to be highly conserved across different models of epilepsy and patients. CREB was predicted as one of the main up-stream transcription factors regulating gene expression during acute and chronic phases and inhibition of CREB reduced seizure severity in the intraamygdala kainic acid model. SignificanceOur findings suggest the intraamygdala kainic acid model faithfully replicates key molecular features of human drug-resistant temporal lobe epilepsy and provides potential rationale target approaches for disease-modification through new insights into the unique and shared gene expression landscape in experimental epilepsy. Key point boxO_LIMore genes show expression changes shortly following intraamygdala kainic acid-induced status epilepticus when compared to established epilepsy. C_LIO_LIThe intraamygdala kainic acid mouse model mimics closely the gene expression landscape in the brain of patients with temporal lobe epilepsy. C_LIO_LISupressed calcium signalling in the brain as common feature across experimental models of epilepsy and patients with temporal lobe epilepsy. C_LIO_LICREB is a major up-stream transcription factor during early changes following status epilepticus and once epilepsy is established. C_LI

neuroscience↗

bioRxiv2019

Large-scale changes to mRNA polyadenylation in temporal lobe epilepsy

The molecular mechanisms that shape the gene expression landscape during the development and maintenance of chronic states of brain hyperexcitability are incompletely understood. Here we show that cytoplasmic mRNA polyadenylation, a posttranscriptional mechanism for regulating gene expression, undergoes widespread reorganisation in temporal lobe epilepsy. Specifically, over 25% of the hippocampal transcriptome displayed changes in their poly(A) tail in mouse models of epilepsy, particular evident in the chronic phase. The expression of cytoplasmic polyadenylation binding proteins (CPEB1-4) was found to be altered in the hippocampus in mouse models of epilepsy and temporal lobe epilepsy patients and CPEB4 target transcripts were over-represented among those showing poly(A) tail changes. Supporting an adaptive function, CPEB4-deficiency leads to an increase in seizure severity and neurodegeneration in mouse models of epilepsy. Together, these findings reveal an additional layer of gene expression control during epilepsy and point to novel targets for seizure control and disease-modification in epilepsy.

neuroscience↗