赛庚素对 Orai 介导的 Ca2+ 进入的调控--神经退行性病变的新靶点。

IF 4.3 2区 生物学 Q2 CELL BIOLOGY
Gaiti Hasan
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引用次数: 0

摘要

畸变的 Ca2+ 信号是多种神经退行性综合征的早期特征,包括阿尔茨海默病和帕金森病(AD 和 PD),以及脊髓性脊髓侧索硬化症(Spinocebellar Ataxias)等罕见遗传疾病。针对异常 Ca2+ 信号同时允许神经元正常 Ca2+ 信号的治疗策略一直是一个挑战。在最近的一项研究中,Princen 等人在 tauP301L 多发性硬化症细胞模型中进行了一项筛选,以寻找能特异性改善所观察到的 Ca2+ 过量进入的药物。他们发现了一类被称为 ReS19-T 的化合物,该化合物能与 Septins 相互作用,而 Septins 以前被认为是存储操作的 Ca2+ 进入通道 Orai 的调节剂。对细胞模型、小鼠模型和人类 iPSC 衍生神经元的药物治疗减轻了与 tauP301L 相关的细胞和系统缺陷。对药物治疗和非药物治疗条件下的肽蛋白丝结构进行比较表明,过量的 Ca2+ 进入是肽蛋白丝结构异常导致 ER-PM 接触异常的结果。此前,人们已经认识到膜接触对于维持精确的细胞信号传导的重要性。然而,Septin丝组织ER-PM连接以通过Orai调节Ca2+进入的分子机制仍有待充分了解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Septin regulation of Orai-mediated Ca2+ entry - a novel target for neurodegeneration

Septin regulation of Orai-mediated Ca2+ entry - a novel target for neurodegeneration

Aberrant Ca2+ signaling is an early hallmark of multiple neurodegenerative syndromes including Alzheimer's and Parkinson's disease (AD and PD) as well as classes of rare genetic disorders such as Spinocebellar Ataxias. Therapeutic strategies that target aberrant Ca2+ signals whilst allowing normal neuronal Ca2+ signals have been a challenge. In a recent study Princen et al., performed a screen in the tauP301L cell model of AD for drugs that could specifically ameliorate the excess Ca2+ entry observed. They identified a class of compounds referred to as ReS19-T that interact with Septins, previously identified as regulators of the Store-operated Ca2+ entry channel Orai. Drug treatment of the cellular model, a mouse model and human iPSC derived neurons alleviate cellular and systemic deficits associated with tauP301L. Comparison of Septin filament architecture in disease conditions with and without the drug treatment indicate that excess Ca2+ entry is a consequence of abnormal Septin filament architecture resulting in aberrant ER-PM contacts. The importance of membrane contacts for maintaining precise cellular signaling has been recognized previously. However, the molecular mechanism by which Septin filaments organize the ER-PM junctions to regulate Ca2+ entry through Orai remains to be fully understood.

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来源期刊
Cell calcium
Cell calcium 生物-细胞生物学
CiteScore
8.70
自引率
5.00%
发文量
115
审稿时长
35 days
期刊介绍: Cell Calcium covers the field of calcium metabolism and signalling in living systems, from aspects including inorganic chemistry, physiology, molecular biology and pathology. Topic themes include: Roles of calcium in regulating cellular events such as apoptosis, necrosis and organelle remodelling Influence of calcium regulation in affecting health and disease outcomes
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