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 in compensatory reinnervation and disease progression was recently suggested in a mouse model of amyotrophic lateral sclerosis. Here, Dr Gaëlle Bruneteau (ICM researcher and clinician at the “Pitié-Salpêtrière” hospital) and her colleagues sought to investigate whether the histone deacetylase 4 pathway plays a role in muscle compensatory reinnervation in patients with amyotrophic lateral sclerosis and thus contributes to disease outcome differences. They 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. They showed that the proportion of reinnervated neuromuscular junctions was significantly higher in long-term survivors than in patients with rapidly progressive disease. The researchers 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. These results show 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.
Bruneteau G. et al. 2013, muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis : potential role in reinnervation abiblity and disease progression, Brain 136; 2359-2368.
From left to right :
– vacant neuromuscular junction, completely denervated
– reinnervated neuromuscular junction
– normal neuromuscular junction (control patient)
Left and right: confocal microscopy of SLA neuromuscular junctions. In red, the post-synaptic apparatus and in green the axon terminal
Photo crédit : INSERM