Muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis: potential role in reinnervation ability and disease progression

肌萎缩侧索硬化 神经再支配 医学 肌肉萎缩 利鲁唑 运动神经元 神经科学 内科学 生物 萎缩 解剖 疾病
作者
Gaëlle Bruneteau,Thomas Simonet,Stéphanie Bauché,Nathalie Mandjee,Edoardo Malfatti,Emmanuelle Girard,Marie‐Laure Tanguy,Anthony Béhin,F. Khiami,Elhadi Sariali,Caroline Hell-Remy,François Salachas,Pierre‐François Pradat,Emmanuel Fournier,Lucette Lacomblez,Jeanine Koenig,Norma B. Romero,Bertrand Fontaine,Vincent Meininger,Laurent Schaeffer,Daniel Hantaı̈
出处
期刊:Brain [Oxford University Press]
卷期号:136 (8): 2359-2368 被引量:124
标识
DOI:10.1093/brain/awt164
摘要

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.
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