在渐冻症临床前模型中,包裹磷脂酰肌醇衍生物的纳米颗粒通过长期激活 TRPML1 溶酶体通道促进神经保护和功能改善。

IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Valentina Tedeschi, Valeria Nele, Valeria Valsecchi, Serenella Anzilotti, Antonio Vinciguerra, Laura Zuccaro, Maria Josè Sisalli, Chiara Cassiano, Nunzia De Iesu, Giuseppe Pignataro, Lorella Maria Teresa Canzoniero, Anna Pannaccione, Giuseppe De Rosa, Agnese Secondo
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引用次数: 0

摘要

背景和目的:肌萎缩性脊髓侧索硬化症(ALS)是一种进行性神经退行性疾病,目前无法治愈,运动神经元变性会导致自主性骨骼肌萎缩。从分子角度看,肌萎缩侧索硬化症的特征是蛋白质聚集、突触和细胞器功能障碍以及 Ca2+ 平衡失调。值得关注的是,自噬功能障碍正在成为 ALS 治疗的主要假定靶点之一。通过适当刺激主要溶酶体通道之一的 TRPML1,可以对这一清洁过程进行调节。然而,PI(3,5)P2 激活的 TRPML1 保持活性构象的开放概率较低。为了克服这一缺点,我们开发了一种基于脂质的 PI(3,5)P2 制剂,其治疗潜力已在体外和体内 ALS 模型中进行了测试:实验方法:通过运动神经细胞中的贴片钳电生理学和 Fura-2AM 视频成像,确定了 PI(3,5)P2 脂基制剂(F1 和 F2)对 TRPML1 活性的药效学特性。在筛选出能稳定 TRPML1 活性的制剂后,对最有效的制剂 F1 进行了体内研究,以测量 SOD1G93A ALS 小鼠的神经肌肉功能和存活率,从而确定其治疗特性。主要结果 F1(而不是单独的 PI(3,5)P2)稳定了溶酶体通道 TRPML1 的开放状态,并增加了细胞内钙浓度([Ca2+]i)的持续性。然后,F1 能有效延缓 SOD1G93A 小鼠运动神经元的丧失,改善神经支配内植物和肌肉性能,平均延长整体寿命 10 天。值得注意的是,F1通过恢复PI(3,5)P2水平,防止了ALS小鼠的神经胶质增生和自噬功能障碍:我们用于递送 PI(3,5)P2 的新型自组装脂质制剂在 ALS 临床前模型中发挥了神经保护作用,主要是通过稳定 TRPML1 的活性来调节自噬功能障碍。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Nanoparticles encapsulating phosphatidylinositol derivatives promote neuroprotection and functional improvement in preclinical models of ALS via a long-lasting activation of TRPML1 lysosomal channel.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease currently incurable, in which motor neuron degeneration leads to voluntary skeletal muscle atrophy. Molecularly, ALS is characterized by protein aggregation, synaptic and organellar dysfunction, and Ca2+ dyshomeostasis. Of interest, autophagy dysfunction is emerging as one of the main putative targets of ALS therapy. A tune regulation of this cleansing process is affordable by a proper stimulation of TRPML1, one of the main lysosomal channels. However, TRPML1 activation by PI(3,5)P2 has low open probability to remain in an active conformation. To overcome this drawback we developed a lipid-based formulation of PI(3,5)P2 whose putative therapeutic potential has been tested in in vitro and in vivo ALS models. Pharmacodynamic properties of PI(3,5)P2 lipid-based formulations (F1 and F2) on TRPML1 activity have been characterized by means of patch-clamp electrophysiology and Fura-2AM video-imaging in motor neuronal cells. Once selected for the ability to stabilize TRPML1 activity, the most effective preparation F1 was studied in vivo to measure neuromuscular function and survival of SOD1G93A ALS mice, thereby establishing its therapeutic profile. F1, but not PI(3,5)P2 alone, stabilized the open state of the lysosomal channel TRPML1 and increased the persistence of intracellular calcium concentration ([Ca2+]i). Then, F1 was effective in delaying motor neuron loss, improving innervated endplants and muscle performance in SOD1G93A mice, extending overall lifespan by an average of 10 days. Of note F1 prevented gliosis and autophagy dysfunction in ALS mice by restoring PI(3,5)P2 level. Our novel self-assembling lipidic formulation for PI(3,5)P2 delivery exerts a neuroprotective effect in preclinical models of ALS mainly regulating dysfunctional autophagy through TRPML1 activity stabilization.

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来源期刊
Pharmacological research
Pharmacological research 医学-药学
CiteScore
18.70
自引率
3.20%
发文量
491
审稿时长
8 days
期刊介绍: Pharmacological Research publishes cutting-edge articles in biomedical sciences to cover a broad range of topics that move the pharmacological field forward. Pharmacological research publishes articles on molecular, biochemical, translational, and clinical research (including clinical trials); it is proud of its rapid publication of accepted papers that comprises a dedicated, fast acceptance and publication track for high profile articles.
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