Muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis: potential role in reinnervation ability and disease progression
Muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis: potential role in reinnervation ability and disease progression
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DOI：
10.1093/brain/awt164
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发表时间：
2013-08-01
期刊：
影响因子：
14.5
通讯作者：
Hantai, Daniel
中科院分区：
文献类型：
--
作者：
Bruneteau, Gaelle;Simonet, Thomas;Hantai, Daniel
肌萎缩性侧索硬化症是一种典型的快速进行性神经退行性疾病，影响运动神经元，导致进行性肌肉麻痹和死亡，通常因呼吸衰竭，时间为3-5年。一些患者病情进展缓慢，生存期延长，但其潜在机制尚不清楚。利鲁唑是唯一被批准的治疗方法，只能适度延长生存期，对肌肉功能没有影响。在疾病的早期阶段，运动神经元的损失最初通过侧支神经再生来补偿，但随着时间的推移，这种补偿失败，导致进行性肌肉萎缩。肌组蛋白去乙酰化酶4及其调控因子microRNA-206在肌萎缩性侧索硬化症小鼠模型（携带人类超氧化物歧化酶基因突变的转基因小鼠）中的代偿性神经再生和疾病进展中起着至关重要的作用。在这里，我们试图研究microrna -206-组蛋白去乙酰化酶4通路是否在肌萎缩侧索硬化症患者的肌肉代偿性再神经支配中发挥作用，从而导致疾病结局的差异。研究人员利用高分辨率共聚焦成像技术对11例肌萎缩性侧索硬化症患者的肌肉样本进行神经肌肉连接研究，其中包括5例长期存活患者。我们发现，在长期存活的患者中，再神经肌肉连接的比例明显高于疾病快速进展的患者。我们分析了参与再神经支配过程的肌肉候选基因的表达，发现组蛋白去乙酰化酶4的上调在疾病快速进展的患者中明显更大，并且与肌肉再神经支配的程度和功能结局呈负相关。相反，组蛋白去乙酰化酶4的调节因子microRNA-206在两组患者中均上调，但与疾病进展或神经再生无关。我们得出结论，肌萎缩侧索硬化症患者的肌肉表达组蛋白去乙酰化酶4可能是肌肉神经再生和疾病进展的关键因素。特异性组蛋白去乙酰化酶4抑制剂可能成为增强肌萎缩侧索硬化症运动表现和减缓疾病进展的治疗方法。
Amyotrophic lateral sclerosis is a typically rapidly progressive neurodegenerative disorder affecting motor neurons leading to progressive muscle paralysis and death, usually from respiratory failure, in 3-5 years. Some patients have slow disease progression and prolonged survival, but the underlying mechanisms remain poorly understood. Riluzole, the only approved treatment, only modestly prolongs survival and has no effect on muscle function. In the early phase of the disease, motor neuron loss is initially compensated for by collateral reinnervation, but over time this compensation fails, leading to progressive muscle wasting. The crucial role of muscle histone deacetylase 4 and its regulator microRNA-206 in compensatory reinnervation and disease progression was recently suggested in a mouse model of amyotrophic lateral sclerosis (transgenic mice carrying human mutations in the superoxide dismutase gene). Here, we sought to investigate whether the microRNA-206-histone deacetylase 4 pathway plays a role in muscle compensatory reinnervation in patients with amyotrophic lateral sclerosis and thus contributes to disease outcome differences. We studied muscle reinnervation using high-resolution confocal imaging of neuromuscular junctions in muscle samples obtained from 11 patients with amyotrophic lateral sclerosis, including five long-term survivors. We showed that the proportion of reinnervated neuromuscular junctions was significantly higher in long-term survivors than in patients with rapidly progressive disease. We analysed the expression of muscle candidate genes involved in the reinnervation process and showed that histone deacetylase 4 upregulation was significantly greater in patients with rapidly progressive disease and was negatively correlated with the extent of muscle reinnervation and functional outcome. Conversely, the proposed regulator of histone deacetylase 4, microRNA-206, was upregulated in both patient groups, but did not correlate with disease progression or reinnervation. We conclude that muscle expression of histone deacetylase 4 may be a key factor for muscle reinnervation and disease progression in patients with amyotrophic lateral sclerosis. Specific histone deacetylase 4 inhibitors may then constitute a therapeutic approach to enhancing motor performance and slowing disease progression in amyotrophic lateral sclerosis.