Cofilin inhibition ameliorates PIEZO2 and AMPA dysfunction in a mouse model of Angelman syndrome.

IF 4 2区 医学 Q1 NEUROSCIENCES
Luis O Romero,Manisha Bade,Elisa Carrillo,Sonia Paz-López,Syed A M Hasan,William James Antonisamy,Vasanthi Jayaraman,Zahoor A Shah,Valeria Vásquez,Julio F Cordero-Morales
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Abstract

Angelman syndrome (AS) is a neurogenetic disorder characterized by motor coordination and cognitive deficits. In AS, hippocampal neurons show reduced filamentous actin, a decrease we also reported in dorsal root ganglia (DRG) neurons, along with impaired mechanosensitive ion channel activity. Currently, there are no pharmacological targets to prevent the decrease of filamentous actin in AS. Here, we utilize a first-in-class selective cofilin inhibitor (SZ-3) to restore PIEZO2 function in DRG neurons and glutamate-evoked currents in hippocampal neurons from AS mice. Using atomic force microscopy, we demonstrate that inhibiting cofilin, an actin-severing protein, with SZ-3 increases cellular stiffness by stabilizing the actin cytoskeleton. Furthermore, systemic administration of SZ-3 in male and female AS mice enhances their performance in the rotarod and T-maze tests. These findings support that cytoskeletal dysregulation contributes to impaired ion channel function and behavioral deficits, and that actin-binding proteins could serve as a target for enhancing motor coordination and spatial learning in AS.Significance Statement Angelman syndrome (AS) is a severe neurogenetic disorder characterized by significant motor and cognitive impairments; however, effective treatments remain elusive. Recent evidence implicates deficits in the mechanosensitive PIEZO2 channel and AMPA receptor function, as well as cytoskeletal abnormalities in AS pathology. Our study identifies cofilin, an actin-binding protein, as a regulator of ion channel function. We demonstrate that pharmacological inhibition of cofilin restores PIEZO2 channel and AMPA receptor activities, enhances neuronal excitability, and improves motor coordination and learning in a mouse model of AS. These findings reveal a novel mechanism by which actin dynamics influence sensory and cognitive function.
抑制Cofilin可改善Angelman综合征小鼠模型中PIEZO2和AMPA功能障碍。
Angelman综合征(AS)是一种以运动协调和认知缺陷为特征的神经遗传性疾病。在AS中,海马神经元显示丝状肌动蛋白减少,我们也报道了背根神经节(DRG)神经元的减少,同时机械敏感离子通道活性受损。目前,尚无阻止AS中丝状肌动蛋白减少的药理靶点。在这里,我们利用一种一流的选择性cofilin抑制剂(SZ-3)来恢复AS小鼠DRG神经元中的PIEZO2功能和海马神经元中的谷氨酸诱发电流。使用原子力显微镜,我们证明了抑制cofilin(一种肌动蛋白切断蛋白)与SZ-3通过稳定肌动蛋白细胞骨架增加细胞刚度。此外,全身给药SZ-3可以提高雄性和雌性AS小鼠在旋转棒和t迷宫测试中的表现。这些发现支持细胞骨架失调导致离子通道功能受损和行为缺陷,并且肌动蛋白结合蛋白可以作为增强as运动协调和空间学习的靶标。Angelman综合征(AS)是一种严重的神经遗传性疾病,以显著的运动和认知障碍为特征;然而,有效的治疗方法仍然难以捉摸。最近的证据表明,在as病理中,机械敏感性PIEZO2通道和AMPA受体功能的缺陷以及细胞骨架异常。我们的研究确定了肌动蛋白结合蛋白cofilin作为离子通道功能的调节因子。我们证明了在AS小鼠模型中,cofilin的药物抑制可以恢复PIEZO2通道和AMPA受体的活性,增强神经元的兴奋性,改善运动协调和学习。这些发现揭示了肌动蛋白动力学影响感觉和认知功能的新机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Neuroscience
Journal of Neuroscience 医学-神经科学
CiteScore
9.30
自引率
3.80%
发文量
1164
审稿时长
12 months
期刊介绍: JNeurosci (ISSN 0270-6474) is an official journal of the Society for Neuroscience. It is published weekly by the Society, fifty weeks a year, one volume a year. JNeurosci publishes papers on a broad range of topics of general interest to those working on the nervous system. Authors now have an Open Choice option for their published articles
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