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Expression of Circ_Satb1 Is Decreased in Mesial Temporal Lobe Epilepsy and Regulates Dendritic Spine Morphology
Andreia Gomes-Duarte1, Morten T Venø2,3, Marina de Wit1
1Affiliated Partner of the European Reference Network EpiCARE, Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
Abstract:
Mesial temporal lobe epilepsy (mTLE) is a chronic disease characterized by recurrent seizures that originate in the temporal lobes of the brain. Anti-epileptic drugs (AEDs) are the standard treatment for managing seizures in mTLE patients, but are frequently ineffective. Resective surgery is an option for some patients, but does not guarantee a postoperative seizure-free period. Therefore, further insight is needed into the pathogenesis of mTLE to enable the design of new therapeutic strategies. Circular RNAs (circRNAs) have been identified as important regulators of neuronal function and have been implicated in epilepsy. However, the mechanisms through which circRNAs contribute to epileptogenesis remain unknown. Here, we determine the circRNA transcriptome of the hippocampus and cortex of mTLE patients by using RNA-seq. We report 333 differentially expressed (DE) circRNAs between healthy individuals and mTLE patients, of which 23 circRNAs displayed significant adjusted p-values following multiple testing correction. Interestingly, hippocampal expression of circ_Satb1, a circRNA derived from special AT-rich sequence binding protein 1 (SATB1), is decreased in both mTLE patients and in experimental epilepsy. Our work shows that circ_Satb1 displays dynamic patterns of neuronal expression in vitro and in vivo. Further, circ_Satb1-specific knockdown using CRISPR/CasRx approaches in hippocampal cultures leads to defects in dendritic spine morphology, a cellular hallmark of mTLE. Overall, our results identify a novel epilepsy-associated circRNA with disease-specific expression and previously unidentified cellular effects that are relevant for epileptogenesis.
Insights
This study identifies circ_Satb1 as a novel circular RNA implicated in mesial temporal lobe epilepsy (mTLE). Reduced circ_Satb1 levels in mTLE patients correlate with cellular changes relevant to epileptogenesis.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Mesial temporal lobe epilepsy (mTLE) is a chronic neurological disorder often resistant to anti-epileptic drugs and surgery.
- Circular RNAs (circRNAs) are emerging as key regulators in neuronal function, with potential roles in epilepsy pathogenesis.
- Understanding the specific mechanisms of circRNAs in epileptogenesis is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To investigate the circRNA transcriptome in the hippocampus and cortex of mTLE patients.
- To identify specific circRNAs involved in mTLE pathogenesis.
- To elucidate the cellular functions of identified epilepsy-associated circRNAs.
Main Methods:
- RNA sequencing (RNA-seq) was employed to analyze the circRNA transcriptome of brain tissue from mTLE patients and healthy controls.
- Differential expression analysis was performed to identify significant circRNAs.
- CRISPR/CasRx technology was used to knockdown circ_Satb1 in hippocampal cultures to assess its cellular effects.
Main Results:
- 333 differentially expressed circRNAs were identified between mTLE patients and controls, with 23 reaching statistical significance.
- Hippocampal expression of circ_Satb1, derived from the SATB1 gene, was significantly decreased in mTLE patients and in experimental epilepsy models.
- Knockdown of circ_Satb1 in hippocampal cultures resulted in dendritic spine morphology defects, a known cellular hallmark of mTLE.
Conclusions:
- circ_Satb1 is a novel, disease-specific circular RNA associated with mTLE.
- Decreased circ_Satb1 expression contributes to cellular abnormalities relevant to mTLE pathogenesis.
- circ_Satb1 represents a potential therapeutic target for mTLE.
