Lo Adrian C, Rajan Nicholas, Gastaldo Denise, Telley Ludovic, Hilal Muna L, Buzzi Andrea, Simonato Michele, Achsel Tilmann, Bagni Claudia
Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.
Department of Neurosciences and Leuven Brain Institute, KU Leuven, Leuven, Belgium.
EMBO Rep. 2021 Apr 7;22(4):e51404. doi: 10.15252/embr.202051404. Epub 2021 Mar 28.
Status epilepticus (SE) is a condition in which seizures are not self-terminating and thereby pose a serious threat to the patient's life. The molecular mechanisms underlying SE are likely heterogeneous and not well understood. Here, we reveal a role for the RNA-binding protein Fragile X-Related Protein 2 (FXR2P) in SE. Fxr2 KO mice display reduced sensitivity specifically to kainic acid-induced SE. Immunoprecipitation of FXR2P coupled to next-generation sequencing of associated mRNAs shows that FXR2P targets are enriched in genes that encode glutamatergic post-synaptic components. Of note, the FXR2P target transcriptome has a significant overlap with epilepsy and SE risk genes. In addition, Fxr2 KO mice fail to show sustained ERK1/2 phosphorylation induced by KA and present reduced burst activity in the hippocampus. Taken together, our findings show that the absence of FXR2P decreases the expression of glutamatergic proteins, and this decrease might prevent self-sustained seizures.
癫痫持续状态（SE）是一种癫痫发作不能自行终止的疾病，因此对患者生命构成严重威胁。SE潜在的分子机制可能具有异质性且尚未完全了解。在此，我们揭示了RNA结合蛋白脆性X相关蛋白2（FXR2P）在SE中的作用。Fxr2基因敲除小鼠对 kainic 酸诱导的 SE 表现出特异性的敏感性降低。与相关mRNA的下一代测序相结合的FXR2P免疫沉淀表明，FXR2P的靶标在编码谷氨酸能突触后成分的基因中富集。值得注意的是，FXR2P靶标转录组与癫痫和SE风险基因有显著重叠。此外，Fxr2基因敲除小鼠未能表现出由KA诱导的持续ERK1/2磷酸化，并且海马体中的爆发活动减少。综上所述，我们的研究结果表明，FXR2P的缺失会降低谷氨酸能蛋白的表达，而这种降低可能会阻止自我持续发作。
