Abstract
BackgroundSpinal Muscular Atrophy (SMA) is one of the most common inherited causes of infant death and is caused by the loss of functional survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene. One of the treatment strategies for SMA is to induce the expression of the protein from the homologous SMN2 gene, a rescuing paralog for SMA.Methods and resultsHere we demonstrate the promise of pharmacological modulation of SMN2 gene by BAY 55-9837, an agonist of the vasoactive intestinal peptide receptor 2 (VPAC2), a member of G protein coupled receptor family. Treatment with BAY 55-9837 lead to induction of SMN protein levels via activation of MAPK14 or p38 pathway in vitro. Importantly, BAY 55-9837 also ameliorated disease phenotype in severe SMA mouse models.ConclusionOur findings suggest the VPAC2 pathway is a potential SMA therapeutic target.
Highlights
Spinal Muscular Atrophy (SMA) is one of the most common inherited causes of infant death and is caused by the loss of functional survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene
This results in the production of more SMN protein, which can partially compensate for the loss of SMN1 gene and to moderate the disease phenotype
In order to assess the potential of VPAC-2 receptor activation in the regulation of SMN gene expression; human NT2, mouse MN-1 cells and SMA I patient fibroblasts were treated with VPAC2 receptor agonist BAY 55-9837 (25 μM) for 24 h and subsequently harvested for western blot analysis
Summary
Spinal Muscular Atrophy (SMA) is one of the most common inherited causes of infant death and is caused by the loss of functional survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene. Treatment with BAY 55-9837 lead to induction of SMN protein levels via activation of MAPK14 or p38 pathway in vitro. SMA is caused by the pathologic reduction in survival of motor neuron (SMN) protein levels due to deletions and mutations in SMN1 gene [3]. We show that treatment with BAY 55-9837 increases brain and spinal cord SMN protein levels as well as improving disease phenotype and survival in a severe SMA mouse model. Our results provide further evidence that p38 MAPK pathway activators act as potential therapeutic compounds for the treatment of SMA and identify the VPAC pathway as one means of achieving such activation
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