RGD Reference Report - Muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis: potential role in reinnervation ability and disease progression. - Rat Genome Database

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

Authors: Bruneteau, G  Simonet, T  Bauche, S  Mandjee, N  Malfatti, E  Girard, E  Tanguy, ML  Behin, A  Khiami, F  Sariali, E  Hell-Remy, C  Salachas, F  Pradat, PF  Fournier, E  Lacomblez, L  Koenig, J  Romero, NB  Fontaine, B  Meininger, V  Schaeffer, L  Hantai, D 
Citation: Bruneteau G, etal., Brain. 2013 Aug;136(Pt 8):2359-68. doi: 10.1093/brain/awt164. Epub 2013 Jul 3.
RGD ID: 9681450
Pubmed: PMID:23824486   (View Abstract at PubMed)
DOI: DOI:10.1093/brain/awt164   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
amyotrophic lateral sclerosis severityIEP 9681450 RGD 
amyotrophic lateral sclerosis severityISOHDAC4 (Homo sapiens)9681450; 9681450 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hdac4  (histone deacetylase 4)

Genes (Mus musculus)
Hdac4  (histone deacetylase 4)

Genes (Homo sapiens)
HDAC4  (histone deacetylase 4)


Additional Information