DOK7 Gene Therapy Enhances Neuromuscular Junction Innervation and Motor Function in Aged Mice
DOK7 Gene Therapy Enhances Neuromuscular Junction Innervation and Motor Function in Aged Mice
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DOI：
10.1016/j.isci.2020.101385
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发表时间：
2020-08-21
期刊：
影响因子：
5.8
通讯作者：
Yamanashi, Yuji
中科院分区：
文献类型：
--
作者：
Ueta, Ryo;Sugita, Satoshi;Yamanashi, Yuji
神经肌肉连接处（NMJ）是运动神经元和骨骼肌之间的重要突触，其肌肉失神经支配与年龄相关的运动损伤有关。因此，改善老年NMJs的肌肉神经支配可能是治疗损伤的有效治疗策略。我们之前已经证明，肌肉蛋白Dok-7在NMJ的形成中起着至关重要的作用，事实上，它在肌肉中的强制表达会增加NMJ。此外，在肌萎缩性侧索硬化症（ALS）小鼠模型中，治疗性给予编码人类DOK7的腺相关病毒载体（DOK7基因治疗）抑制肌肉去神经支配并增强运动活动。在这里，我们发现DOK7基因治疗可以显著增强老年小鼠的运动功能和肌肉力量以及NMJ神经支配。此外，与对照组相比，治疗组小鼠的复合肌肉动作电位（CMAP）振幅显著增加，表明神经肌肉传递增强。因此，旨在增强NMJ神经支配的疗法有可能治疗与年龄相关的运动障碍。
Muscle denervation at the neuromuscular junction (NMJ), the essential synapse between motor neuron and skeletal muscle, is associated with age-related motor impairment. Therefore, improving muscle innervation at aged NMJs may be an effective therapeutic strategy for treating the impairment. We previously demonstrated that the muscle protein Dok-7 plays an essential role in NMJ forma-tion, and, indeed, its forced expression in muscle enlarges NMJs. Moreover, therapeutic administration of an adeno-associated virus vector encoding human Dok-7 (DOK7 gene therapy) suppressed muscle denervation and enhanced motor activity in a mouse model of amyotrophic lateral sclerosis (ALS). Here, we show that DOK7 gene therapy significantly enhances motor function and muscle strength together with NMJ innervation in aged mice. Furthermore, the treated mice showed greatly increased compound muscle action potential (CMAP) ampli-tudes compared with the controls, suggesting enhanced neuromuscular transmis-sion. Thus, therapies aimed at enhancing NMJ innervation have potential for treating age-related motor impairment.