Pumilio-1介导的血脑屏障中Claudin-5的翻译控制。

IF 5.9 1区 医学 Q1 NEUROSCIENCES
Yosuke Hashimoto, Chris Greene, Nicole Hanley, Natalie Hudson, David Henshall, Kieron J Sweeney, Donncha F O'Brien, Matthew Campbell
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引用次数: 0

摘要

Claudin-5是血脑屏障上最重要的紧密连接蛋白之一。单核苷酸多态性 rs10314 位于 Claudin-5 的 3'- 非翻译区,已被证明是精神分裂症的一个风险因素。在这里,我们发现 pumilio RNA 结合蛋白 pumilio-1 负责 rs10314 介导的 claudin-5 调节。围绕 rs10314 的 RNA 序列与典型的 pumilio 结合序列高度同源,带有 rs10314 的 claudin-5 mRNA 由于无法与 pumilio-1 结合,产生的蛋白质减少了 25%。在应激条件下,Pumilio-1 形成细胞膜颗粒,而 claudin-5 mRNA 似乎会优先积聚在这些颗粒中。此外,我们还在精神障碍或癫痫患者的人脑组织内皮细胞中观察到颗粒状的 pumilio-1,同时发现 claudin-5 mRNA 水平升高/积聚,这表明 claudin-5 的翻译抑制可能以脑区特异性的方式发生。这些发现确定了claudin-5翻译处理的一个关键调节因子,以及它的失调如何可能与神经和神经精神疾病有关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pumilio-1 mediated translational control of claudin-5 at the blood-brain barrier.

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.

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来源期刊
Fluids and Barriers of the CNS
Fluids and Barriers of the CNS Neuroscience-Developmental Neuroscience
CiteScore
10.70
自引率
8.20%
发文量
94
审稿时长
14 weeks
期刊介绍: "Fluids and Barriers of the CNS" is a scholarly open access journal that specializes in the intricate world of the central nervous system's fluids and barriers, which are pivotal for the health and well-being of the human body. This journal is a peer-reviewed platform that welcomes research manuscripts exploring the full spectrum of CNS fluids and barriers, with a particular focus on their roles in both health and disease. At the heart of this journal's interest is the cerebrospinal fluid (CSF), a vital fluid that circulates within the brain and spinal cord, playing a multifaceted role in the normal functioning of the brain and in various neurological conditions. The journal delves into the composition, circulation, and absorption of CSF, as well as its relationship with the parenchymal interstitial fluid and the neurovascular unit at the blood-brain barrier (BBB).
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