Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland.
Science Foundation Ireland Research Centre for Chronic and Rare Neurological Diseases, FutureNeuro, Royal College of Surgeons in Ireland (RCSI), University of Medicine and Health Sciences, Dublin, Ireland.
Fluids Barriers CNS. 2024 Jun 19;21(1):52. doi: 10.1186/s12987-024-00553-5.
Claudin-5 is one of the most essential tight junction proteins at the blood-brain barrier. A single nucleotide polymorphism rs10314 is located in the 3'-untranslated region of claudin-5 and has been shown to be a risk factor for schizophrenia. Here, we show that the pumilio RNA-binding protein, pumilio-1, is responsible for rs10314-mediated claudin-5 regulation. The RNA sequence surrounding rs10314 is highly homologous to the canonical pumilio-binding sequence and claudin-5 mRNA with rs10314 produces 25% less protein due to its inability to bind to pumilio-1. Pumilio-1 formed cytosolic granules under stress conditions and claudin-5 mRNA appeared to preferentially accumulate in these granules. Added to this, we observed granular pumilio-1 in endothelial cells in human brain tissues from patients with psychiatric disorders or epilepsy with increased/accumulated claudin-5 mRNA levels, suggesting translational claudin-5 suppression may occur in a brain-region specific manner. These findings identify a key regulator of claudin-5 translational processing and how its dysregulation may be associated with neurological and neuropsychiatric disorders.
紧密连接蛋白 5 是血脑屏障中最重要的紧密连接蛋白之一。单核苷酸多态性 rs10314 位于紧密连接蛋白 5 的 3'-非翻译区，已被证明是精神分裂症的风险因素。在这里，我们表明 pumilio RNA 结合蛋白 pumilio-1 负责 rs10314 介导的紧密连接蛋白 5 调节。rs10314 周围的 RNA 序列与典型的 pumilio 结合序列高度同源，并且由于不能与 pumilio-1 结合，rs10314 产生的 claudin-5 mRNA 减少了 25%。在应激条件下，pumilio-1 形成细胞质颗粒，而 claudin-5 mRNA 似乎优先在这些颗粒中积累。此外，我们观察到来自精神障碍或癫痫患者的人脑组织中的内皮细胞中存在颗粒状 pumilio-1，并且 claudin-5 mRNA 水平增加/积累，表明翻译 claudin-5 抑制可能以脑区特异性方式发生。这些发现确定了 claudin-5 翻译加工的关键调节剂，以及其失调如何与神经和神经精神障碍相关。
