摘要

Defects in the phosphoinositide 3-kinase (PI3K) pathway are shared characteristics in several brain disorders, including the inherited intellectual disability and autism spectrum disorder, fragile X syndrome (FXS). PI3K signaling therefore could serve as a therapeutic target for FXS and other brain disorders. However, broad inhibition of such a central signal transduction pathway involved in essential cellular functions may produce deleterious side effects. Pharmacological strategies that selectively correct the overactive components of the PI3K pathway while leaving other parts of the pathway intact may overcome these challenges. Here, we provide the first evidence that disease mechanism-based PI3K isoform-specific inhibition may be a viable treatment option for FXS. FXS is caused by loss of the fragile X mental retardation protein (FMRP), which translationally represses specific messenger RNAs, including the PI3K catalytic isoform p110β. FMRP deficiency increases p110β protein levels and activity in FXS mouse models and in cells from subjects with FXS. Here, we show that a novel, brain-permeable p110β-specific inhibitor, GSK2702926A, ameliorates FXS-associated phenotypes on molecular, cellular, behavioral, and cognitive levels in two different FMRP-deficient mouse models. Rescued phenotypes included increased PI3K downstream signaling, protein synthesis rates, and dendritic spine density, as well as impaired social interaction and higher-order cognition. Several p110β-selective inhibitors, for example, a molecule from the same chemotype as GSK2702926A, are currently being evaluated in clinical trials to treat cancer. Our results suggest that repurposing p110β inhibitors to treat cognitive and behavioral defects may be a promising disease-modifying strategy for FXS and other brain disorders.

译文

磷酸肌醇 3-激酶 (PI3K) 通路的缺陷是几种大脑疾病的共同特征,包括遗传性智力障碍和自闭症谱系障碍,脆性 X 综合征 (FXS)。因此,PI3K 信号可以作为 FXS 和其他脑部疾病的治疗靶点。然而,广泛抑制这种参与基本细胞功能的中央信号转导通路可能会产生有害的副作用。选择性纠正 PI3K 通路过度活性成分,同时保持通路其他部分完整的药理策略可能会克服这些挑战。在此,我们提供了基于疾病机制的 PI3K 亚型特异性抑制可能是 FXS 可行的治疗选择的第一个证据。FXS 是由翻译抑制特定信使 rna,包括 PI3K 催化异构体 p110 β 的脆性 X 智力低下蛋白 (FMRP) 的丢失引起的。FMRP 缺乏增加了 FXS 小鼠模型和 FXS 受试者细胞中 p110 β 蛋白水平和活性。在这里,我们展示了一种新的、脑渗透性的 p110 β 特异性抑制剂,GSK2702926A,在分子、细胞、行为上改善了 FXS 相关的表型, 和两种不同 FMRP 缺陷小鼠模型的认知水平。被拯救的表型包括增加的 PI3K 下游信号、蛋白质合成率和树突棘密度,以及受损的社会互动和高阶认知。例如,几种 p110 β 选择性抑制剂,一种与 GSK2702926A 来自同一化学类型的分子,目前正在治疗癌症的临床试验中进行评估。我们的结果表明,重新利用 p110 β 抑制剂来治疗认知和行为缺陷可能是 FXS 和其他脑部疾病的一个有前途的疾病修饰策略。

Phosphoinositide-3 Kinase

神经 临床研究术语
概述  :  

磷脂酰肌醇是真核细胞膜的组成成分,磷脂参与多种细胞过程的调节,包括细胞增殖、存活、细胞骨架组织、囊泡运输、葡萄糖转运和血小板功能。PI3K主要分为3个类型,分别为class Ⅰ PI3Ks、class Ⅱ PI3Ks 和class Ⅲ PI3Ks。根据其底物的结合特点,class Ⅰ PI3Ks 又可以分为两个次级亚型,即ⅠA 型和ⅠB 型。ⅠA 类PI3K 是异源二聚蛋白,每个蛋白由一个p110 的催化亚基和一个p85 调节亚基组成。 对心血管的影响

phosphoinositide    [,fɔsfəui'nəusitaid] 

释    义    n. 磷酸肌醇

例    句 

The role of phosphoinositide 3-kinase signal pathway in airway smoothmuscle cells proliferation in asthma.磷脂酰肌醇3激酶途径在哮喘大鼠气道平滑肌细胞增殖中的作用。

 

kinase    英 [ˈkaɪneɪz]  美 [ˈkɪnneɪz] 

释    义    n. [生化] 激酶;致活酶

例    句 

The scientists successfully identified the small enzyme molecule responsible, a gene called focaladhesion kinase.科学家成功分离出这种小小的酶分子,基因学上称之为局部粘着激酶。

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